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Studies in the synthetic utility of the dianion of B-ketoesters Huckin, Stuart Nicholas 1973

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c l STUPIES IN THE SYNTHETIC UTILITY OF THE DIANION OF 3-KETOESTERS by STUART NICHOLAS HUCKIN B.Sc. (Hons.), University of Sussex, 1968 A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in the Department of Chemistry We accept t h i s thesis as conforming to the required standard THE UNIVERSITY OF A p r i l , BRITISH COLUMBIA 1973 In p r e s e n t i n g t h i s t h e s i s i n p a r t i a l f u l f i l m e n t o f t h e r e q u i r e m e n t s f o r an advanced degree a t the U n i v e r s i t y o f B r i t i s h C olumbia, I agree t h a t the L i b r a r y s h a l l make i t f r e e l y a v a i l a b l e f o r r e f e r e n c e and s t u d y . I f u r t h e r agree t h a t p e r m i s s i o n f o r e x t e n s i v e c o p y i n g o f t h i s t h e s i s f o r s c h o l a r l y p urposes may be g r a n t e d by the Head o f my Department o r by h i s r e p r e s e n t a t i v e s . I t i s u n d e r s t o o d t h a t c o p y i n g o r p u b l i c a t i o n o f t h i s t h e s i s f o r f i n a n c i a l g a i n s h a l l n o t be a l l o w e d w i t h o u t my w r i t t e n p e r m i s s i o n . Department The U n i v e r s i t y o f B r i t i s h Columbia Vancouver 8, Canada 1173. Date u A/vrJL ABSTRACT. Some of the reactions of the dianion of B-ketoesters were investigated. The dianion of methyl acetoacetate (132), prepared by sequential reaction of methyl acetoacetate with sodium hydride and n-butyllithium, was reacted with a va r i e t y of aldehydes and ketones to give 6-hydroxy-B-ketoesters (150) i n moderate y i e l d . The a l d o l products 150 derived from aromatic aldehydes and ketones were found to be thermally unstable and were converted to t r i m e t h y l s i l y l ether derivatives for cha r a c t e r i s a t i o n purposes. The acylation of dianion 132 was also investigated, and a modified procedure developed which allowed the preparation of 8,6-diketoesters i n f a i r y i e l d . When aromatic esters were employed as acyla t i n g agents, the product i s o l a t e d was found to be a mixture of diketoester and diketoacid. The reaction of dianion 132 with n i t r i l e s was b r i e f l y investigated, and shown to be a f e a s i b l e method of producing Y~ u nsaturated 6-amino-8-ketoesters. F i n a l l y , with dihaloalkanes, dianion 132 gave a mixture of c y c l i c alkylated products and bis - B-ketoesters. Procedures for the optimising of the y i e l d s of each of these classes of compounds were developed. i i i TABLE OF CONTENTS Abstract i i Table of Contents i i i L i s t of Tables v L i s t of Schemes v i Acknowledgements v i i Introduction 1 H i s t o r i c a l Background The Synthetic Value of g-Dicarbonyl Compounds 3 The Dianion of g-Dicarbonyl Compounds 8 The Development of a Method of Generating the Dianion of g-Ketoesters Choice of Reaction Conditions: A Review of 31 some Non-nucleophilic Bases The Preparation and A l k y l a t i o n of the Dianion 41 of g-Ketoesters Results and Discussion The Reaction of A l k y l l i t h i u m Compounds with 48 Sodio Methyl Acetoacetate Aldo l Reaction of the Dianion of g-Ketoesters 56 Attempted Michael Reactions of the Dianion of 72 g-Ketoesters Claisen Condensation of the Dianion of 76 g-Ketoesters i v A l k y l a t i o n of the Dianion of B-Ketoesters with Dihaloalkanes Reaction of N i t r i l e s with the Dianion of B-Ketoesters Experimental General The Reaction of A l k y l l i t h i u m Compounds with the Monoanion of B-Ketoesters Aldol Reactions of the Dianion of B-Ketoesters Claisen Condensations of the Dianion of B-Ketoesters A l k y l a t i o n of the Dianion of B-Ketoesters with Dihaloalkanes Reaction of N i t r i l e s with the Dianion of B-Ketoesters Bibliography Spectral Appendix V L i s t of Tables Table I A l k y l a t i o n of D i a l k a l i g-Diketones i n 16 Liquid Ammonia II Aldol Condensations of D i a l k a l i g-Diketones 18 i n Liquid Ammonia III Acylations of g-Diketones i n Liquid Ammonia 22 IV Aroylations of g-Diketones Employing 24 Sodium Hydride i n Refluxing 1,2-Dimethoxyethane V Claisen Condensations of D i a l k a l i 28 g-Ketoaldehydes VI A l k y l a t i o n of Sodio L i t h i o Methyl 46 Acetoacetate i n Tetrahydrofuran VII Aldol Reactions of Sodio L i t h i o Methyl 59 Acetoacetate i n Tetrahydrofuran VIII M u l t i p l i c i t y of the nmr Absorptions of 62 the a and y Protons of some Substituted 6-Hydroxy-g-Ketoesters IX The Chemical S h i f t s of the g-Protons of 68 some Substituted Styrenes X The Claisen Condensation of Sodio L i t h i o Methyl Acetoacetate 82 v i L i s t of Schemes Scheme I Some Reactions of the Monoanion of Ethyl 5 Acetoacetate. II The Synthesis of Marrubiin 6 III The Synthesis of T r i s p o r i c Acid E 7 IV The Canonical Forms of 10 1-Phenylbutane-l,3-dione V Some Reaction of the Dianion of 12 g-diketones VI The Al k y l a t i o n of Dipotassio 14 Hexane-2,4-dione VII The Benzoylation of D i a l k a l i 27 g-ketcaldehydes VIII The Aldol Condensation of the Dianion 29 of Butane-1,3-dione IX Some Reactions of the Dianion of Ethyl 30 Acetoacetate X The Acylation of Ester Enolates 33 XI Some Reactions of the Dianion of 36-Carboxylic Acids XII Attempts to Form the Dianion of 39 Dimethylnitrosamine XIII Postulated Decomposition of Methyl 55 3-(prop-2-enyl)-2-oxocylohexanecarboxylate Upon Electron Impact XIV The Thermal Decomposition of 69 g-Hydroxyacids XV The Biosynthesis of Phenolic Compounds 77 XVI The Synthesis of Methyl O r s e l l i n a t e from 87 Methyl Acetoacetate XVII The Reaction of Sodio L i t h i o Methyl 91 Acetoacetate with Dihaloalkanes v i i Acknowledgements. I wish to express my sincere thanks to Dr. Larry Weiler for the encouragement and guidance he has given me throughout the course of this research and during the preparation of this manuscript. My thanks are also extended to John F. Kingston, R. Balaji Rao and Frank W.B. Skinner for their tolerance during the course of this research and for their many helpful suggestions. -1-INTRODUCTION. Organic compounds are synthesised for a great many reasons. Often, they are prepared because they are natural products, or because they possess a novel or unusual structure, and frequently, because t h e i r construction represents a challenge to the s k i l l and ingenuity of the organic chemist. Synthetic organic chemistry has now progressed to the extent that i t i s no longer s u f f i c i e n t for a synthesis to be merely successful, i t should also be elegant and d i r e c t . An excellent example of a t o t a l synthesis of a natural product, which has achieved widespread recognition as possessing such q u a l i t i e s , i s the synthesis of chlorophyll (_1) accomplished by R.B. Woodward and coworkers."1" 1 Particulary i n the synthesis of poly-functional natural products, such as c h l o r o p h y l l , a high degree of s e l e c t i v i t y i s often required to perform the desired transformations, and i t i s only careful planning of the synthetic sequence that w i l l produce an elegant and pleasing - 2 -r e s u l t . To be able to design such a synthesis, or even a simple, u t i l i t a r i a n method of producing a compound, i t i s necessary to s c r u t i n i s e a large number of reactions as to th e i r s u i t a b i l i t y i n the synthetic sequence, and t h i s requires a wide knowledge of both the scope and the l i m i t a t i o n s of each reaction. Perhaps the most important, and c e r t a i n l y the most frequently used reactions i n organic chemistry are those in-which carbon-carbon bonds are formed. The subject of t h i s d i s s e r t a t i o n i s an outline of the attempts to delineate the scope of a reaction which allows the formation of a variety; of carbon-carbon bonds, namely the reactions of the dianion of beta-ketoesters. Although there are already documented a myriad ways of forming carbon-carbon bonds an additional method w i l l surely fi n d a p p l i c a b i l i t y , for without choice elegance becomes unattainable. -3-HISTORICAL BACKGROUND. The Synthetic Value of g-Dicarbonyl Compounds. It has long been known that the hydrogen atoms on the a-carbon atom of g-dicarbonyl compounds are r e l a t i v e l y 2 a c i d i c . This was reported by Geuther i n 1863, who, whilst investigating the mechanism of the Claisen condensation of ethyl acetate, treated ethyl acetoacetate (2) with sodium ethoxide i n anhydrous ethanol to form the sodium s a l t of ethyl acetoacetate (3), equation 1. I t was shortly a f t e r t h i s , that Wislicenus reported i n a lengthy 3 paper an extensive study of the properties of ethyl acetoacetate (2_) which was s i g n i f i c a n t i n that not only was the n u c l e o p h i l i c i t y of ethyl sodioacetoacetate (3) f i r s t reported, namely i t s reaction with iodoethane to give ethyl 2-ethylacetoacetate (4_) , but the author foresaw the value of g-ketoesters as synthetic intermediates. The analagous 0) 2 3 0 0 (2) 3 4 - 4 -reactions of B-diketones were not reported u n t i l 1894 when 4 Claisen reported the synthesis of 2-methylpentanedione (6) from pentanedione (5_) and methyl iodide i n the presence of sodium carbonate, equation 3. There then followed a period of over f i f t y years during which the reactions of B-dicarbonyl compounds were explored and rapidly u t i l i s e d to a considerable extent, much as Wislecenus had predicted. A few examples of other nucleophilic reactions of ethyl sodioacetoacetate (3_) are shown i n scheme I; these : reactions were chosen to provide a comparison with the analagous reactions of methyl lithiosodioacetoacetate, which w i l l be ; discussed l a t e r . . It i s d i f f i c u l t to appreciate the f u l l s i g n i f i c a n c e of the synthetic applications of ethyl acetoacetate and other B-dicarbonyl compounds as t h e i r uses have been manifold, yet the l i t e r a t u r e pertaining to t h e i r reactions has not been reviewed (perhaps because of the daunting task such a review would present). This synthetic u t i l i t y could be amply i l l u s t r a t e d , almost ad infinitum, and may be demonstrated by two recent examples; the synthesis of marrubiin (IS), a diterpene lactone from Marrubiin vulgare}^ and of a t r i s p o r i c (3) 5 6 -5-Scheme I -6-aci'd 24_, the p r i n c i p a l sex hormone of Mucor mucedo and Bjakeslea t r i s p o r a . ^ In the former synthesis, a key intermediate, enedione 21_, was prepared by a modified 12 Robinson annelation reaction between 2-methylhexane-l,3-rdione (20) and methyl 3-oxopent-4-enoate (19), which i n turn had been derived from methyl acetoacetate (16) by the Nazarov , 1 3 procedure. Scheme II -7-In the synthesis of (+) - 7 ( t ) , 9 ( t ) - t r i s p o r i c acid B (24), a Michael addition of diketoester 22_ to ethyl v i n y l ketone gave triketoe s t e r 23_ which could be c y c l i s e d , v i a an al d o l reaction with concomittant dehydration to t r i s p o r i c acid 24. Scheme III CH 302C 22 t-BuOK / THF Me.OK / MeOH -8-The Dianion of g-Dicarbonyl Compounds. U n t i l 1958, there was no generally applicable reaction which induced f u n c t i o n a l i s a t i o n at the y-carbon atom of g-dicarbonyl compounds. One reaction of l i m i t e d u t i l i t y was the formation of ethyl 4-brcmoacetoacetate (26) from ethyl 2-bromoacetate (25), when the l a t t e r was allowed to 14 stand for a considerable time. 0 0 0 0 - V V 2 H 5 r ^ O C 2 H 5 C4> Br Br 25 26 This rearrangement has been shown to be induced by the presence 15 of hydrogen bromide and a i r (oxygen), and does not appear to be universal for y-halo-g-dicarbonyl compounds; neither ethyl 2-chloroacetoacetate nor 3-bromopentanedione rearrange 16 under s i m i l a r conditions. 17 It was observed by Hauser that the dipotassio s a l t s of two g-diketones, 1-phenylbutane-l,3-dione (29) and pentane-2,4-dione (3_0) , could be obtained by treatment of the diketone with potassium amide i n l i q u i d ammonia. In the former case t h i s was achieved by d i r e c t addition of s o l i d 27_ to the amide i n l i q u i d ammonia sol u t i o n , whilst with the l a t t e r , the ammonium s a l t of pentanedione 28_ was preformed and t h i s 18 added to the base. R NH3 R 0 C6H5CH2Cl R Q Q (5) 2 7 . R=C6H5 2 8 . R=CH3 2 9 . R=C6H5 3 0 . R=CH3 31, R-C6H5 3 2 . R=CH3 These dipotassio s a l t s react r a p i d l y with one equivalent of benzyl chloride to give only the compounds 3_1 and 32, alkylated at the y p o s i t i o n . of 1-phenylbutane-l,3-dione was rigorously proven to be 31. Molecular weight determination showed i t to be a mono-benzylated product, whilst a mixed melting point determination with 2-benzyl-l-phenylbutane-l, 3r-dione showed i t not to be the a alkylated d e r i v a t i v e . Independent synthesis of 31^ was achieved v i a a Claisen type condensation of methyl hydrocinnamate (33) with the sodium s a l t of acetophenone ( 3 4 ) , and a mixed melting point of the products from both sources was not depressed. The structure of the product from the a l k y l a t i o n 0 + 0 (6) 3 3 3 4 31 Additional data which confirmed the structure to be 31 was the -10-melting point of the copper chelate of the product and that of the pyrazole (35) derived from the product, which were i n good agreement with the l i t e r a t u r e values of those derivatives, of 31. HN N 3 5 19 > Although i t was subsequently shown by nmr that i n solution most of the charge of dianion 2_9_ resided on the oxygen atoms, which would indicate that 29a i s the major contributor of the four possible canonical forms (29a-d), i t i s perhaps easiest to v i s u a l i s e the s a l t as a dicarbanion (29d), to 20 emphasise the high r e a c t i v i t y of the y ~ c a r b o n atom. Scheme IV 0" 0 " o- 0 2 9 a 29b Q 0 " •6n5 29c C6H5 0 0 29d -11-A measure of the r e a c t i v i t y of these dipotassio s a l t s may be gained by comparing the rate of t h e i r a l k y l a t i o n to that of the a l k y l a t i o n of the simple monoanions of 6-diketones; the l a t t e r often proceeds very slowly, even at elevated temperatures whilst rapid a l k y l a t i o n of the dipotassio s a l t s occurs at low temperatures. So great i s t h i s difference i n r e a c t i v i t y , that even when 29_ i s treated with an excess of a l k y l a t i n g agent no substitution at the a - p o s i t i o n i s observed. In addition to t h i s high degree of r e g i o - s p e c i f i c i t y , the a l k y l a t i o n reaction exhibits a s i g n i f i c a n t degree of s t e r e o - s e l e c t i v i t y ; treatment of the dianion of l-phenylpentane-2,4-dione with 1-chloro-l-phenylethane gave only the erythro product in d i c a t i n g a high degree of assymetric 21 induction occurs during the reaction. 17 Hauser also reported i n t h i s f i r s t communication,, the acylation of the dipotassio s a l t s with methyl benzoate to give triketones 36_ and 37_, the phenylation of 3_0 with bromobenzene, i n which benzyne i s intermediate, to give 38, the carbonation of 2_9 to give diketoacid 3_9 and the a l d o l condensation of 29_ with benzaldehyde, the r e s u l t i n g diketoalcohol 40 was subsequently dehydrated to the unsaturated diketone 41, scheme V. In a l l these reactions, substitution occurs only at the y carbon atom. The generality of t h i s procedure of generating the dipotassio s a l t as a method of f u n c t i o n a l i s i n g g-dicarbonyl' compounds i n the y position has been demonstrated by i t s 22 23 application to g-ketoaldehydedes, g-ketoesters, -12-Scheme V 0 0 0 R C6H5 36, R=C6H5 37, R=CH3 Q Q 38> R=CH3 C 6 H 5 C 0 2 C H 3 C6H5Br R C6H5CHO 0 0 29, R=C5H5 30, R=CH3 0 0 OH 0 0 R " OH 39. R=C6H5 p-TsOH R 0 0 6n5 41 1 R=CgiHg -13-24 B-ketolactones, and other related carbonyl compounds, which have included 3-iminoketones (in p a r t i c u l a r N-phenyl 25 2627 28 iminoketones), B-ketosulphones, ' and imides. The Y ~ a l k y l a t i o n of dicarbonyl compounds by t h i s method has been f u l l y investigated by Hauser and coworkers, 20 and the relevant l i t e r a t u r e ( u n t i l 1966) has been reviewed. The y i e l d s of alkylated B-diketones obtained v i a the dianion vary widely, but generally are f a i r to good. I t was found, however, that the y i e l d s were dependent upon the nature of the a l k a l i metal amide used to generate the dianion. In general, i t was found that the dipotassio s a l t and the disodio 29 s a l t gave comparable r e s u l t s (with the exception of pentane-2,4-dione, whose disodio s a l t i s much more soluble i n 30 l i q u i d ammonia than i t s dipotassio salt.) The d i l i t h i o s a l t s have not been used extensively for a l k y l a t i o n , and those reactions which have been reported indicate a lower r e a c t i v i t y , and consequently lower y i e l d , than either the dipotassio or 3 0a disodio s a l t s . This reduced r e a c t i v i t y , which i s probably due to the higher covalent character of the lithium-carbon bond, appears to apply only for a l k y l a t i o n reactions as i t has been reported that for Claisen and a l d o l condensations with enolisable 31 32 esters and ketones, d i l i t h i u m s a l t s give better y i e l d s . ' The r e g i o - s p e c i f i c i t y of the a l k y l a t i o n of B-diketones, i n that reaction occurs only at the y p o s i t i o n , has already, been mentioned, but i t has been reported that the reaction i s even more re g i o - s e l e c t i v e . Where the two y positions of a • B-diketone are unequally substituted, as i n the case of hexane-2,4-dione (42), two isomeric dianions are possible, 43 and 44_, which i n turn could lead to two d i f f e r e n t products upon a l k y l a t i o n 4_5 and £6. I t has been found that generally Scheme VI 42 KNH, NH<-RX t 0 0 0 44 RX 0 0 R 45 46 R a l k y l a t i o n at the lea s t substituted y p o s i t i o n predominates. In the methylation of the disodio s a l t of hexane-2,4-dione (42), the product mixture, obtained i n 56% y i e l d , contains heptane-3 , 5-dione (£5_, R=Me) and 5-methylhexane-2,4-dione (46, R=Me) i n the r a t i o 89:11. 33 S i m i l a r l y , the benzylation of 2-acetyl c y c l i c ketones 47_ gave only those products (48) i n 34 which a l k y l a t i o n had occurred at the methyl group. 1) K N H 2 / N H 3 t 0 0 < C H ^ 2) C 6 H 5 C H 2 C l 47.n=2or3 C 6 H 5 (7) /48.n = 2or3 -15-The alky l a t i o n s of 3-ketoaldehydes have also been 22 24 35 investigated, ' ' and the y i e l d s , although generally lower than those obtained for 3-diketones presumably because of the d i f f i c u l t y of i s o l a t i n g these more unstable dicarbonyl compound are s t i l l f a i r to good. To overcome t h i s i s o l a t i o n d i f f i c u l t y , the alkylated ketoaldehydes have frequently been converted to more stable derivatives p r i o r to i s o l a t i o n , and the i n c l u s i o n of another step tends to lower the o v e r a l l y i e l d . The procedur has been s l i g h t l y modified for 3-ketoaldehydes; the substrate was usually added to the l i q u i d ammonia-amide solution as the monosodio s a l t . This was necessary to avoid the reaction of the aldehyde with the ammonia, and other competing side reactions (e.g. a l d o l condensations of the monoanion with any unmetallated aldehyde). However, the a l k y l a t i o n of 3-ketoesters under these conditions of a l k a l i metal amide i n l i q u i d ammonia give only poor y i e l d s of alkylated e s t e r s , Table I, presumably because of; the low temperature of the reaction or because amidolysis of the ester function also occurs. 1 -16-Table 1. Al k y l a t i o n Of D i a l k a l i g-Ketoesters i n Liquid Ammonia. 0 0 1) M N H 2 / N H 3 (, R \ c 2 H 5 < 8 ) ' V "OC 2 H R 5 2) R'X R' X T R 48 49 M R R' -X Yi e l d ( % ) Reference Na H CH 3I "Low" 36 K H CH3I 36, 37 23 K H EtI 27, 29 23 L i H n-BuBr 0 36 ... Na H n-BuBr 0 23 K H n-BuBr 0 36 Na K C g H 5 C K 2 C I 41 36 K H C 6H 5CH 2C1 0 23 K , C 6H 5 C 6H 5CH 2C1 44 23 K H n-C 3H 7 63 77 K H C 6H 5CH 2Br 65 77 Only one instance has been reported i n which the a l k y l a t i o n of a g-ketoester under these conditions has been observed to occur i n high y i e l d . The benzylation of g-ketolactone 51_ has 24 been reported to give 5_2 i n 90% y i e l d s However, i n the same communication i t was also reported that under e s s e n t i a l l y the -17-0. 1) K N H 2 / N H 3 0 (9) 2) RX R' 0 51»R=CH 3 5 4 . R=C2H 5 52 , R = C H 3 » R = C 6 H 5 C H 2 5 3 , R = C H 3 , R ' = C H 3  5 5 J R = C 2 H I J I R =CgHgCH 2 same c o n d i t i o n s methylation of the same lactone (51) t o 53_ could only be e f f e c t e d i n 39% y i e l d , and t h a t the b e n z y l a t i o n of i t s homolog _54_ proceeds to giv e only 18% of the corresponding product 55. v i a c a r b o x y l a t i o n , C l a i s e n and a l d o l condensations of t h e i r . 17 d i a n i o n s , i n i t i a l l y reported by Kauser, has sin c e been thoroughly i n v e s t i g a t e d . The d i p o t a s s i o s a l t s of (3-diketones undergo a l d o l condensations w i t h ketones and aldehydes having no hydrogen atoms on the carbon atom a to the carbonyls to g i v e reasonable y i e l d s of the corresponding hydroxydiketone 17 32 37 (Table I I ) , ' ' but w i t h ketones and aldehydes t h a t do possess such e n o l i s a b l e hydrogen atoms no a l d o l products could be , i s o l a t e d . The. f a i l u r e of these r e a c t i o n s was p o s t u l a t e d t o : b e due to proton t r a n s f e r from the ketone or aldehyde to the 38 d i a n i o n s a l t . Since l i t h i o e t h y l a c e t a t e , and l i t h i o 39 4 0 t - b u t y l acetate, but not sodio e t h y l a c e t a t e , had been reported to condense w i t h acetophenone, s u b s t i t u t i o n of the d i l i t h i o s a l t of the B-diketones was made, and the a l d o l The s u b s t i t u t i o n of the g-diketones at the y p o s i t i o n c o n d e n s a t i o n w i t h t h e e n o l i s a b l e k e t o n e s was found t o p r o c e e d , a l b e i t i n lower y i e l d s t h a n w i t h t h e n o n - e n o l i s a b l e k e t o n e s . T a b l e I I . A l d o l C o n d e n s a t i o n s o f D i a l k a l i 3 -Diketones i n L i q u i d Ammonia. 0 0 0 MNH9/ NHo 0 0 OH * R R" 2 — ^ ~ R ^ ^ R " OO' R '' 2 7 , R=C6H5 5 6 5 7 2 8 , R=CH3 R R« R" M Y i e l d ( % ) R e f e r e n c e C 6 H 5 C 6 H 5 H K 28 17 C 6 H 5 2-MeOCgHt, H K 49 32 C 6 H 5 C 6 H 5 C 6 H 5 K 73 32 C G K 5 E-ClCgH,, C 6 K 5 K 69 32 CH 3 C 5 H 5 C 6 H 5 K 73 32 CH 3 £-ClC 6H 4 C 6 H 5 K 52 32 C 6 H 5 C 6 H 5 CH 3 L i 40 32 C 6 H 5 ~(CH 2) 5 - I L i 34 32 C 6 H 5 C 6H 5CH=CH C 6 H 5 K 66 37 I t was a p p a r e n t t h a t t h e c a r b o x y l a t i o n o f t h e d i a n i o n s o f 3 - d i k e t o n e s c o u l d not be performed i n l i q u i d ammonia s o l u t i o n , as c a r b o n d i o x i d e , r e a c t s w i t h ammonia t o form ammonium carbamate. C o n s e q u e n t l y , i n t h e i n i t i a l a t t e m p t s t o -19-g e n e r a t e d i k e t o c a r b o x y l i c a c i d s , t h e d i p o t a s s i o s a l t o f 1 - p h e n y l b u t a n e - l , 3-dione (29.) was i s o l a t e d from t h e ammonia s o l u t i o n , suspended i n e t h e r and t r e a t e d w i t h e x c e s s s o l i d 17 49 c a r b o n d i o x i d e . Subsequent i n v e s t i g a t i o n showed t h a t t h e d i s o d i o s a l t gave s u p e r i o r y i e l d s , and a l l f u r t h e r c a r b o x y l a t i o n s were performed u s i n g sodium s a l t s . The 17 49 s i g n i f i c a n c e o f t h e s e c o m m u n i c a t i o n s , ' a s i d e from t h e s y n t h e t i c v a l u e as a r e l a t i v e l y e f f i c i e n t method o f p r o d u c i n g 3 , 6 - d i k e t o a c i d s , i s t h a t t h e y r e p r e s e n t t h e f i r s t r e a c t i o n o f 3 - d i c a r b o n y l d i a n i o n s i n s o l v e n t s o t h e r t h a n l i q u i d ammonia. A c y l a t i o n o f 3 - d i k e t o n e s has been t h e s u b j e c t o f more i n v e s t i g a t i o n t h a n e i t h e r o f t h e two p r e v i o u s r e a c t i o n s . 17 31 41-45 ' ' T h i s i s p r o b a b l y due, a t l e a s t i n p a r t , t o t h e d i f f i c u l t i e s e n c o u n t e r e d d u r i n g a t t e m p t s t o s y n t h e s i s e 1 , 3 , 5 - t r i k e t o n e s e f f i c i e n t l y . These t r i k e t o n e s a r e o f c o n s i d e r a b l e i n t e r e s t as p o s t u l a t e d i n t e r m e d i a t e s i n t h e b i o s y n t h e s i s o f p h e n o l i c compounds.^ The major d i f f i c u l t y , w h i c h o c c u r s i n any s y n t h e s i s o f p o l y - c a r b o n y l compounds i n v o l v i n g a n i o n s , .i.e_. a c y l a t i o n , a r i s e s from t h e f a c t t h a t t h e i n i t i a l c o n d e n s a t i o n p r o d u c t ( f o r example 61) p o s s e s s e s a more a c i d i c hydrogen atom t h a n t h e monoanion 59 of t h e s t a r t i n g d i c a r b o n y l compound. Thus p r o t o n t r a n s f e r o c c u r s , e q u a t i o n 13, and one a d d i t i o n a l m o l e c u l e o f t h e d i a n i o n i s quenched ( p r o t o n a t e d t o g i v e t h e monoanion) f o r each m o l e c u l e o f t h e p r o d u c t t h a t i s formed. S i n c e t h e a l k o x i d e i o n t h a t i s formed d u r i n g t h e c o n d e n s a t i o n i s n o t a s u f f i c i e n t l y s t r o n g base t o r e g e n e r a t e t h e d i a n i o n £0 from -20-t h e monoanion 5j9, t h e maximum y i e l d o f p r o d u c t , based on t h e d i c a r b o n y l component, i s f i f t y p e r c e n t . 58 59 60 60 R' 61 0 0 0 0 0 60 R 61 0 0 0 0 0 R ^ V ^ R ' + R^V^SfV (13) 59 ^ ~ 62 0 0 0 0 R - V " ^ ' R ' " ° ' X > R ^ W R ' 04) 59 60 In the i n i t i a l a c y l a t i o n s , 17 a onefold excess of the dianion was employed, and the y i e l d was based upon the degree of conversion of the es t e r , but t h i s approach would be unsatisfactory i n a synthetic sequence where the diketone i s expensive or d i f f i c u l t to obtain. excess base have had only limited success during the condensation of methyl benzoate with 1-phenylbutane-l,3-dione (27) employing three equivalents of potassium amide, the excess base reacted mainly with the es t e r , converting i t to benzamide. Whilst with esters which possess hydrogen atoms on the a carbon atom, excess potassium amide has been found to cause e n o l i s a t i o n 41 of the ester , and consequently gave no condensation. In 32 analogy with the ald o l condensation r e s u l t s , lithium amide 31 was employed, and found to be more s a t i s f a c t o r y , but the yi e l d s of triketone were s t i l l rather poor (Table I I I ) . and coworkers, i s the Y ~a r° y la ti °n o f 3-diketones employing an excess of sodium hydride i n refluxing 1,2-dimethoxyethane as the condensing agent (equation 15). Attempts to overcome t h i s d i f f i c u l t y by addition of A related reaction which was developed by Kauser 43 R NaH / Me0CHoCHo0iMe R ^ ^ A r ( 1 5 ) 0 0 0 ArC0 oR' 58 64 -22-Table I I I . Acylation of D i a l k a l i g-Diketones i n Liquid Ammonia, 0 0 1) MNH2/NH3 0 0 0 R ^ - ^ 2) R'C02R" " R ' A - A ^ R ' «6> 58 63 R R' R" M Yield(%) Reference CH 3 CH 3 CH 2 L i ' 17 44 CH3 n-C 7H 1 5 CH 3 L i 41 44 n-C 7H 1 5 CH3 CH 3 L i 17 44 CH 3 CH 3 L i 38 44 CH 3 n-C,H7 CH3 L i 42 44 CH 3 C 6H 5 CH 3 K 60 a, 53 17, C 6H 5 C bH 5 CH 3 K 58 a, 62, 80 17, C 6H 5 ^CHgOCgH^ CH3 K 61 41 C bH 5 ^ClCgH,, CH 3 K 47 41 C 6H 5 3-pyridyl CH 3 K 40 41 CeH, CH 3 CH 3CH2 L i 45, (66) b 31 C 6H 5 CH 3 CH 2 CH 3 L i 42, (79) b 31 (CH 3) 2CH CH3 L i 43, (88) b 31 C 6H 5 n~Cg HI y CH 3 L i 40 31 CH 3 CH3 CH 3 CH2 L i 45, (59) b 31 CH3 CH ^CH 2 CH3 L i 50 31 Notes a) a r a t i o of dianion to ester of 2:1 was used for these reactions and the y i e l d i s based on conversion of ester, b) the y i e l d i n parentheses i s based on conversion of dianion, allowing for recovered g-diketone. -23-The mechanism of t h i s reaction i s uncertain but i t i s u n l i k e l y that sodium hydride forms the dianion d i r e c t l y , as only one equivalent of hydrogen i s evolved on addition of the sodium hydride. A second equivalent of hydrogen i s evolved 43 on addition of the ester. One suggested mechanism requires a second ionisation of the diketone to be induced v i a a termolecular t r a n s i t i o n state 65_ occurring on the surface of the sodium hydride, with either a simultaneous or subsequent condensation of the dianion so generated. The y i e l d s of triketone produced by t h i s method are generally very good (Table IV), but t h i s method as yet has only been 47 applied to a r o y l a t i o n s . Since i t had been reported that i t was possible to form B-diketones from ketones and esters v i a a Claisen condensation under e s s e n t i a l l y these conditions (equation 17), i t was deemed p l a u s i b l e that these two reactions could be combined, and aroylate a ketone twice to give l i n e a r triketone 68 (equation 18). 0 Ar l /OR* 0 6 5 -24-Table IV. Aroylations of g-Diketones Employing Sodium Hydride i n Refluxing 1,2-Dimethoxyethane. NaH / MeOCH2CH2OMe ArC0 2R' 0 0 (15) R Ar R' Y i e l d Reference C 6H 5 C 6H 5 CH3 87 43 C 6H 5 E ~ C H 3 O C 6 H 4 CH 3 92 43 C 6H 5 CH 3 78 43 C 6H 5 3-pyridyl CH 3 CH 2 69 43 CH3 CH 3 54, 55-60 43, 45 C 5E 5(CH 2)2 CH 3 61 45 CH, E-CHgOCgH^ CH 3 72 45 & , • A ^ - 1 X a?) R OR' MeOCH2CH2OMe R " ^ / ^ U " 66 67 58 0 67 NaH / MeOCH2CH2OMe ArC0 2R (18) This method was found to give the desired triketone 68 i n 43 good y i e l d , but i t s application i s obviously limited to the synthesis of symmetrical triketones. The dianions of 3-diketones have also been condensed with a, 3-unsaturated carbonyl compounds i n a Michael type reaction. R 0 0 2 9 » R=CgH^  3 0 , R=CH3 C s H ^ X 6 9 0 0 C 6 H 5 0 7 0 , R=C6H5 7 1 , R=CH3 ( 1 9 ) However, i t was found that the reaction of dipotassio 1-phenylbutane-l, 3-dione (.29) with 1, 3-diphenylprop-2-en-l-one (69, X=C6H5) gave no Michael addition product, but formed only the a l d o l product 72_. When the unsaturated ketone was changed for the more s t e r i c a l l y hindered chalcone, 3-phenyl-l-(2,4,6-trimethylphenyl)-prop-2-en-l-one (69, X=2,4,6-trimethoxyphenyl), the Michael product 70, X=2,4,6-trimethylphenyl, was formed i n good y i e l d 37 Dipotassio 1-phenylbutane-l,3-dione (29) also f a i l e d to give the Michael product with methyl cinnamate (§9_, X=OCH3), attacking the carbonyl to give triketone 7_3, R=C6H5. The Michael addition was accomplished by making the carbonyl of the ester more s t e r i c a l l y hindered, by using t-butyl cinammate (69^ , X=OC (CH3) 3) . i n the reaction, to give 70, X=OC(CH3) 3 . 4 2 Dipotassio pentane-2,4-dione (30) and methyl > cinnamate (69_, X=OCH3) have been reported to give a mixture of products, both the Michael addition product 71_, X=OCH3, 4 2 and the Claisen condensation product 73_, R=CH3. The Claisen and aldo l condensations of the dianions of (3-ketoaldehydes have also been investigated by Hauser and 48 coworkers. (The carboxylation of butane-1,3-dione has been reported to give no s i g n i f i c a n t amounts of the expected product. ^ ) These condensations are complicated by subsequent reactions of the anticipated products during work up. Frequently, the product isol a t e d from the Y ~ a r o Y l a t i ° n o r these ketoaldehydes i s the pyrone 76. -27-Scheme VII But with 5-phenylpentane-l,3-dione (74_, R=C6H5CH2/ R'=H) •.' the reported product i s the pyridone 77_, formed by reaction of 7_5, R=C6H5CHZ/ R'=H, or i t s mono- or dianion with ammonia. 0 77 The four Claisen condensations reported to t h i s date are summarised below. -28-Table V. Claisen Condensations of D i a l k a l i g-Ketoaldehydes. 6-Ketoaldehyde 74 R R' Product Yield(%) H H aldehyde 7_5, R=H, R'=H 52 C 6H 5CH 2 H pyridone 77 72 H C 6 H 5 pyrone 1S_, R=H, R'=C bH5 50 (53) a H C G H 5 ^ H 2 pyrone 76, R=K, R'=C6H5CH2 60 (63) a. Note: a) the y i e l d s i n parentheses are those obtained using sodium hydride i n r e f l u x i n g 1,2-dimethoxyethane as the condensing agent. The y-aroylation of g-ketoaldehydes has also been accomplished using sodium hydride in re f l u x i n g 1,2-dimethoxyethane; the products obtained are the corresponding pyrones 7_6. This reaction appears to give only marginally better y i e l d s than the l i q u i d ammonia method. The product from the a l d o l condensation of sodio potassio butane-1,3-dione (78) and benzophenone was i s o l a t e d as i t s copper chelate 8_0 i n 67% y i e l d , but attempted hydrolysis of t h i s chelate gave acetal 8^1 rather than the hydroxyaldehyde 79. -29-Scheme VIII 0 0 H 78 (CgH5 ) 2C0 OH 0 0 Cu(OAc) 2 HOAc HO 0 C 6 H 5 81 HoO+ OH 0 0 80 Reactions at the y carbon atom of ethyl acetoacetate, induced v i a the dipotassio s a l t 8_2_ i n l i q u i d 23 ammonia, have been reported by Hauser, but the y i e l d s have not been high. The a l d o l condensation of benzophenone with 8_2 gave in 50% y i e l d the expected hydroxyketoester 83_, the carboxylation of 8_2_ i n ether gave acetonedicarboxylic acid. 49 monoethyl ester (84_) i n 55% y i e l d , but the Claisen condensation of methyl benzoate with 8_2_ gave, after acid 23 treatment, pyrone 8_6 i n only 11% y i e l d (Scheme IX) . - 3 0 -Scheme IX O H 0 0 C6H5 O C 2 H 5 / ~C 02C2H5 X ~ C 0 2 H 8 4 (C6H5)2CO NHo C 0 2 / E t 2 0 0 0 O C o H 2n5 C6H5C02Me 82 NH-; 0 0 0 C 6 H 5 O C 2 H 5 85 H2S04 O H 6n5 86 The Y ~a r° y la ti °n o r ethyl acetoacetate (2) has also been achieved with methyl benzoate, using sodium hydride i n refluxing 1,2-dimethoxyethane, and under these conditions the isolated product i s the diketoacid 8J_, obtained i n 48% y i e l d . 0 0 0 87 -31-THE DEVELOPMENT OF A METHOD OF GENERATING THE DIANION OF B-KETOESTERS. Choice of Reaction Conditions: A Review of Some  Non-nucleophilic Bases. It was recently required i n our laboratory to func t i o n a l i s e B -ketoesters at the y carbon atom i n attempts to synthesise acetogenins, for example resistomycin ( 8 9 ) . ^ 89 It appeared necessary to generate a dianionic intermediate i f reaction at the y carbon atom was to be obtained, (the sodium hydride * dimethoxyethane reaction may not proceed v i a the dianions, and that reaction seems limited to aroylations). It was f e l t that the use of l i q u i d ammonia, as solvent, would not be appropriate for reactions of B-ketoesters, since i t s use would impose two i n t r i n s i c disadvantages; reactions would be limited to those which w i l l proceed at a reasonable rate at low temperature (below -33 9C), '"•V . t and the reactions might be complicated by condensation of the ammonia with reagents or products (vide, ut supra) . This decision not to use l i q u i d ammonia as solvent, coupled with the requirement of a strong base that was also a poor nucleophile (necessary to generate the dianion), i n i t i a l l y appeared to demand a very c a r e f u l choice of reagents and possibly very stringent reaction conditions. With regard to the choice of solvent, two other solvents, d i e t h y l ether and 1,2-dimethoxyethane, had been employed for reactions of the dipotassio s a l t of ethyl 23 49 50 acetoacetate {02) ' but tetrahydrofuran has reportedly better solvating a b i l i t y for anionic species, and thus t h i s l a t t e r solvent was selected. Lithium s a l t s , p a r t i c u l a r l y enolates, have been found to be e a s i l y formed and are generally more soluble 38 39 51 than the corresponding potassium or sodium s a l t s , ' ' and, since i t was desired to have a homogeneous rea c t i o n , the i n i t i a l investigations were designed to produce the d i l i t h i o s a l t of ethyl acetoacetate. The addition of two equivalents of n-butyllithium to a solution of ethyl acetoacetate (2) i n tetrahydrofuran f a i l e d to generate the desired dianion, but appeared to 52 8 0 attack the carbonyl functions ' (see also part IV), and hence a search for an al t e r n a t i v e base possessing high proton abstracting a b i l i t y yet low n u c l e o p h i l i c i t y was i n i t i a t e d . (A comparison of the u t i l i t y of some bases which allegedly 53 possess such a b i l i t y has been very recently reported. ) It has been suggested that the condensation of an-enolate of an ester, for example 91, with an acid c h l o r i d e , - 3 3 -scheme (X), i s one of the most stringent empirical measures of the strength and s e l e c t i v e r e a c t i v i t y desired i n a base (B~) and of the inertness required i n i t s conjugate acid (BH) Scheme X B" R 2 C H C 0 2 C 2 H 5 B H 90 R 2 C C 0 2 C 2Hg 91 C 6 H 5 0 0 R R 92 C6H5COCt O C 2 H 5 Using t h i s reaction as an assay, the f a i l u r e of such bases as a l k y l magnesium hal i d e s , a l k y l l i t h i u m s , sodium ethoxide, sodium hydride and sodium amide has been used to demonstrate 54 the u t i l i t y of a l k a l i triphenyl methanes. (These l a t t e r bases have recently been successfully employed i n our laboratory to alkylate s t e r i c a l l y hindered 3-diketones i n 55 the y p o s i t i o n . ) ; Other bases of lov/ n u c l e o p h i l i c i t y which have found recent applications are the lithium s a l t s of dialkylamines, 56 and include lithium diethylamide, lithium diisopropylamide (9_3),57 lithium N-isopropylcyclohexylamide (9_4),58 lithium 53 dicyclohexylamide (9_5) , lithium 2, 2, 6 ,6-tetramethylpipera.de (96), 53,59 and lith i u m b i s - ( t r i m e t h y l s i l y l ) a m i d e . 60 9 7 N S i ( C H 3 ) 3 Of a l l these bases, only one 93 has been widely employed i n a dianion reaction; i t was used, i n i t i a l l y by 57 Creger, to generate the dianion of 2-methylpropanoic a c i d (99) which could then be alkylated i n high y i e l d s , providing the f i r s t e f f i c i e n t , one step synthesis of alkyldimethylacetic acids (100). > C 0 2 H ^ >C0-2 R+C02H (22) This dianion reaction has also been applied to t o l u i c acids, and permits a l k y l a t i o n of the methyl group i n moderate 61 y i e l d s , equation (23). 9 8 9 9 1 0 0 (23) -35-I t i s i n t e r e s t i n g to note t h a t o r t h o t o l u i c a c i d s g i v e the h i g h e s t y i e l d of a l k y l a t e d p r o d u c t s , w h i l s t the para isomers g i v e b e t t e r y i e l d s than the meta t o l u i c a c i d s , and t h e r e i s a s u f f i c i e n t d i s t i n c t i o n between these p o s i t i o n s t h a t i f t h e r e i s more than methyl group on the phenyl r i n g , the o-methyl group i s s e l e c t i v e l y a l k y l a t e d i n p r e f e r e n c e to e i t h e r a m- or p_- methyl group, and a p_-methyl group i s s i m i l a r l y s e l e c t i v e l y a l k y l a t e d r a t h e r than a m-methyl group. The d i a n i o n of a l k y l a c e t i c a c i d s , 103, R=H, have a l s o been prepared, by means of t h i s base (93), and have been shown to r e a c t w i t h a l k y l h a l i d e s to g i v e o n l y the 6 2 mono - a-alkylated product. . Other d i l i t h i o s a l t s of-c a r b o x y l i c a c i d s have been prepared, and condensed w i t h 6 3 aldehydes and ketones to g i v e 3-hydroxyacids, condensed w i t h 64 formaldehyde to g i v e , a f t e r d e h y d r a t i o n , a - a l k y l a c r y l i c a c i d s , 57 condensed w i t h epoxides, and aminated w i t h 65 O-methylhydroxylamine i n a one step s y n t h e s i s of aminoacids, (Scheme X I ) . In the l a s t f o u r r e a c t i o n s , hexamethylphpsphoramide was used as a c o s o l v e n t to i n c r e a s e the s o l u b i l i t y of the d i a n i o n s . The use of t h i s c o s o l v e n t has been i n v e s t i g a t e d by P f e f f e r and coworkers and found to be v e r y e f f e c t i v e : i n i n c r e a s i n g the r a t e of m e t a l a t i o n of ot-branched a c i d s but i t i s d e l e t e r i o u s i n t h a t i t depressed the y i e l d d u r i n g a l k y l a t i o n . fi 7 Other s t u d i e s by P f e f f e r i n d i c a t e t h a t the major c o n t r i b u t i n g resonance s t r u c t u r e of the d i a n i o n i s 103a i n . which the change i s l o c a l i s e d on the oxygen atoms, (cf -36-Scheme XI HO R' R-R'"R A "C 02H "* ref62 114 R"COR"' R's^ O" R^O" H 2 CO 103 ref 63 r-OH R'-f-C02H R R'x R" 115 H + / A 1) ClSiMe. 116 R=H 2) A ref 70 OSi(CH3)3 Ryk^C0 2H R R R' 118 MeOH J J R C02H 117 0 R ,yAv^C02H R R Rf-119 -37-dipotassio-l-phenylbutane-1,3-dione (29)). R R ! 0 R R: o ,0" 103a 103b This was indicated by the isomerisation of trans-2-hexanoic acid (104) which occurred under the conditions normally employed for dianion formation, whilst other unsaturated acids, i n which the double bond i s separated from the carboxylic acid by several methylene groups, are unaffected by t h i s reaction. 104 1) LiN(i-Pr)2/ THF 2) H30* (24) + 105 106 That the dianion exists i n the form of structure 103a was also indicated by the (unspecified) nmr spectrum of dilithio-2-methyl-3-phenylpropionate (103, R=CH3, R'=C 6H 5CH 2), -38-and further c r e d i b i l i t y for t h i s structure arises from the 69 report of Ainsworth that the dianion from various carboxylic acids could be trapped by chlorotrimethylsilane as t h e i r bis-enol ethers 108. Ryco,H LlN(l"Pr)2 » R'X°" C l S l ( C H 3 ) 3 ^ R W O S i ( C H 3 ) 3 ( 2 5 ) R THF F r V R^OSi(CH3)3 107 103 108 This procedure of quenching the dianion with chlorotrimethylsilane was e f f e c t i v e l y employed to f a c i l i t a t e the i s o l a t i o n of the products from the Claisen condensation of dianion 103, which permitted 3-ketoacids 110 to be prepared i n high y i e l d , the intermediate s i l y l esters 109 being e a s i l y and quantitatively hydrolysed i n neutral ,... 70 conditions. R' 0" D R"C02Me 2) ClSiMer 103 R " ? \ O S i ( C H 3 ) 3 R R' 109 MeOH 0 0 R R 110 (26) A d i f f i c u l t y , similar to that of the nucleophilic attack upon the carbonyl groups of ethyl acetoacetate by 52 71 n-butyllithium, has been reported by Enders during attempts to form an anion i n the a p o s i t i o n of - 3 9 -dimethylnitrosamine (120). The anion 124 could be formed by the addition of n-butyllithium to 120, as evidenced by i t s subsequent reaction with benzophenone, but the metalation competed with nucleophilic attack, and the product i s o l a t e d (from sequential addition of n-butyllithium and benzophenone to 120) was a mixture of carbinol 121 and butanal oxime (122). However, when lithium diisopropylamide was employed as the base, very high y i e l d s of alkylated and a l d o l products could be obtained, in d i c a t i n g a very high conversion of the nitrosamine to i t s anion. Scheme XII <C6H5)2C^ N-N=0 HO 1 121 :=NOH 122 1) n-BuL / THF 2) (C 6H 5) 2CO \ / Li N ( i - P r ) , N-N=0 120 \ \ / N-N=0 124 C 6 H 5 C H O C 6 H 5 N-N=0 OH 125 -40-Hence i t would appear t h a t l i t h i u m d i i s o p r o p y l a m i d e (9_3) might w e l l o b v i a t e the d i f f i c u l t y encountered i n the p r i o r attempt to generate the d i a n i o n of 3 - k e t o e s t e r s , (see p a r t IV, f o r d i s c u s s i o n of use of t h i s b a s e ) . L i t h i u m b i s - ( t r i m e t h y l s i l y l ) amide (97_) was b r i e f l y employed t o form l i t h i o e t h y l a c e t a t e (9_1, R=H) from the • 6 0 e s t e r . However, i t was necessary to use t h i s base a t ver y low temperature (-78°C), and w h i l s t the y i e l d s o f a l d o l condensation products from l i t h i o e t h y l a c e t a t e were good, 5 8 i t was subsequently found t h a t the use of t h i s base c o u l d not be extended to form other e s t e r e n o l a t e s . An i n v e s t i g a t i o n of v a r i o u s a l k y l - s u b s t i t u t e d l i t h i u m amides, i n c l u d i n g l i t h i u m d i i s o p r o p y l a m i d e , showed t h a t l i t h i u m N - i s o p r o p y l c y c l o h e x y l a m i d e (94) was s u p e r i o r t o the other bases i n forming the e n o l a t e of e t h y l hexanoate. The e s t e r e n o l a t e s , prepared by means of t h i s base 9_4_, were found to be unique i n t h a t they c o u l d be warmed to room temperature without undergoing s u b s t a n t i a l s e l f - c o n d e n s a t i o n , ( i f the r e a c t i o n mixture d e r i v e d from any of the othe r bases, i n c l u d i n g 93_ or 9J7, was allowed t o warm s u b s t a n t i a l l y above -78°C, a r a p i d and i r r e v e r s i b l e disappearance of the e s t e r o c c u r r e d , which was a s c r i b e d to s e l f - c o n d e n s a t i o n ) . Quenching the s o l u t i o n w i t h deuterium oxide under a v a r i e t y of c o n d i t i o n s , gave a maximum deuterium i n c o r p o r a t i o n when l i t h i u m N - i s o p r o p y l c y c l o h e x y l a m i d e was employed, but the l e v e l o f deuterium i n c o r p o r a t i o n never exceeded s e v e n t y - f i v e p e r c e n t . T h i s low l e v e l of i n c o r p o r a t i o n was p o s t u l a t e d t o -41-a r i s e from an (unspecified) unusual protonation mechanism, and not from p a r t i a l e n o l i s a t i o n . The l a t t e r explanation was eliminated by the r e s u l t s of an additional experiment; the addition of excess ester to the base, which r a p i d l y gave self-condensation products, showing that an equilibrium between the ester and the enolate was impossible. (Similar low deuterium incorporations have been reported by Creger, ^ when employing lithium diisopropylamide to form d i l i t h i o t o l u i c acid salts) . The. l i t h i o ethyl esters of substituted acetic acids could be alkylated, at room temperature, i n good y i e l d , but l i t h i o ethyl acetate apparently undergoes self-condensation at a rate comparable to that of a l k y l a t i o n and i t was found that t-butyl acetate was more s a t i s f a c t o r y for a l k y l a t i o n . The use of l i t h i o enol esters, formed by the procedure 58 of Rathke, has been extended as a method of preparing 72 a-iodo esters, and of preparing symmetrically substituted 73 succinate esters. The l a t t e r conversion was achieved by the addition of copper (II) s a l t s to a solution of the enolate, analogous, oxidative dimerisations of aldehyde and ketone 74 enolates have also been reported. The Preparation and A l k y l a t i o n of the Dianion of B-Ketoesters. It i s well known that a ketone may be protected from nucleophilic attack during a reaction by conversion to i t s enolate, for example, a s e l e c t i v e conversion of the ester f u n c t i o n a l i t y of B-ketoester 126 to an alcohol was achieved by sequential treatment of 126 with sodium hydride and excess m e t h y l l i t h i u m . -42-75 0 7 yr C 0 2 C H 3 1) NaH 2) MeLi (27) 126 127 S i m i l a r l y , Hauser has p r e v e n t e d c o n d e n s a t i o n o f 3-keto a l d e h y d e s w i t h ammonia by p r e f o r m i n g t h e i r sodium 22 24 35 s a l t s . ' ' The f o r m a t i o n o f t h e d i a n i o n o f t h e s e k e t o a l d e h y d e s must p e r f o r c e p r o c e e d v i a t h e monoanion. A l s o , t h e d i a n i o n o f phenylpropanone (130) has been p r e p a r e d v i a 7 6 t h e monoanion 129. C 6H 5 A 4^ W v^A 4-BULi • 6 n 5 > THF 0 C 6 H 5 ^ A \ ( 2 8 ) 128 129 130 Hence i t was e x p e c t e d t h a t m e t a l a t i o n o f t h e monoanion o f m e t h y l a c e t o a c e t a t e (131).would g i v e t h e d i a n i o n 78 132, and i t was fo u n d t h a t t r e a t m e n t o f m e t h y l a c e t o a c e t a t e (16) w i t h sodium h y d r i d e and n - b u t y l l i t h i u m d i d produce t h e d i a n i o n 132. 1 6 NaH 0CH< THF 0 0 131 n-BuLi 0CH 3 THF 0 0 A ^ A ^ (29) - >r 0CH3 132 -43-Formation of the dianion was confirmed by quenching the reaction with a solution of deuterated t r i f l u o r o a c e t i c acid i n deuterium oxide, which gave incorporation of deuterium' at both the a and y positions. The deuterium at the former position was removed by extraction of the is o l a t e d product into a solution of sodium hydrogen carbonate, followed by a c i d i f i c a t i o n and r e - i s o l a t i o n of the 8-ketoester. After t h i s treatment, i t was found, by nmr and mass spectroscopy, that the methyl acetoacetate contained 0.96 ± 0.03 deuterium atoms per molecule and t h i s deuterium was located only i n the y pos i t i o n . 0 C H 3 16 1) NaH / T H F 2) n-BuLi 3) D Q 0 + h ) N a H C 0 3 |2) H 3 0 + 0 0 D 16b The dianion 132 could be monoalkylated i n the Y position r a p i d l y and i n high y i e l d at 0°C (Table VI), but -44 -a t l o w e r t e m p e r a t u r e s t h e r a t e o f a l k y l a t i o n d e c r e a s e d s h a r p l y ( i n d i c a t i n g o n e o f t h e r e a s o n s f o r t h e l o w y i e l d s o b t a i n e d b y t h e l i q u i d ammonia - a m i d e m e t h o d ) . The nmr and mass s p e c t r a o f t h e i s o l a t e d , a l k y l a t e d p r o d u c t s i n d i c a t e d t h a t r e a c t i o n h ad o c c u r r e d e x c l u s i v e l y a t t h e y p o s i t i o n , a n d f u r t h e r m o r e , nmr s p e c t r a l a n a l y s i s o f t h e c r u d e r e a c t i o n m i x t u r e s f a i l e d t o show a n y e v i d e n c e f o r d i a l k y l a t e d o r O - a l k y l a t e d p r o d u c t s . T h i s p r o c e d u r e a l s o p e r m i t t e d a l k y l a t i o n o f s u b s t i t u t e d g - k e t o e s t e r s . Thus i t was p o s s i b l e , s t a r t i n g w i t h m e t h y l a c e t o a c e t a t e (16) t o g e n e r a t e t h e d i a n i o n 1 3 2 , a l k y l a t e , g e n e r a t e t h e d i a n i o n o f t h i s a l k y l a t e d k e t o e s t e r 133 by a d d i t i o n o f a s e c o n d e q u i v a l e n t o f n - b u t y l l i t h i u m a n d a l k y l a t e a s e c o n d t i m e w i t h a d i f f e r e n t a l k y l a t i n g a g e n t t o g i v e a Y , y - d i s u b s t i t u t e d g - k e t o e s t e r 1 3 4 . 0 0 1 3 2 1) RX 2) n-BuLi ? 0 0 ( 3 0 ) 1 3 3 R'X 0 0 R 1 3 4 -45-However, i t was found that higher y i e l d s were obtained i f the intermediate monoalkylated product was i s o l a t e d and p u r i f i e d p r i o r to performing the second a l k y l a t i o n (Table V I ) . This procedure i s not l i m i t e d to methyl e s t e r s , the dianion of ethyl acetoacetate (82) was alkylated with 3-chloropropene to give ethyl 3-oxohept-6-enoate i n 77% y i e l d . The presence of an a a l k y l substitutent does not appear to a f f e c t the r e a c t i o n , ethyl 2-ethylacetoacetate has also been 52 alkylated i n good y i e l d , (see also part IV for the a l k y l a t i o n of methyl 2-oxocyclohexanecarboxylate). Much e f f o r t has been expended i n optimising conditions for the preparation of B-ketoesters by a v a r i e t y of methods, but nearly a l l the previously employed methods of preparing 7 9 simple y substituted B-ketoesters suffer disadvantages. For instance, the Claisen condensation of an ester with ethyl acetate, except i n a few instances, usually gives four products, two self-condensation and two mixed condensation products which are often d i f f i c u l t to separate. Whilst the a c y l a t i o n of methyl ketones with dimethyl carbonate occasionally gives s u b s t i t u t i o n at the methylene p o s i t i o n rather than the methyl group. The a l k y l a t i o n of the dianion of B-ketoesters appears to be a superior method of preparing y substituted ketoesters, and comparison of Tables I and VI indicates very c l e a r l y t h at, of the two procedures fo r a l k y l a t i n g the dianion, the sodium hydride - n-butyllithium method gives the better y i e l d . The Y-alkylation ° f B-ketoesters using the sodium Table VI. A l k y l a t i o n of Sodio L i t h i o Methyl Acetoacetate i n 7 8 Tetrahydrofuran. 1 ) NaH / THF R 2 8 2) ";BuU * R ( 3 D K \ ^ v ^ s - O C H 3 3) R'X O C H q 135 R 136 R R* X Yi e l d (%) H C H 3 I 81 H C 2H 5 Br 84 H ( C H 3 ) 2 C H I 73 H n-Ci+Hg Br 72 H C H 2 = C H C H 2 Br 83 H C 6 H 5 C H 2 C l 81 n-C 4H 9 C H 2 = C H C H 2 Br 77 n-C 4H 9 C G H 5 C H 2 C l 62 (48) a CH3 C 6 H 5 C H 2 C l 76 C 6 H 5 C H 2 CH 3 , I 86 Note: a) the y i e l d i n parentheses refers to that obtained by successive a l k y l a t i o n of methyl acetoacetate with n-butyl bromide and benzyl chloride, without i s o l a t i o n of the intermediate monoalkylated product. -47-hydride - n-butyllithium procedure has recently been applied to the synthesis of 4-substituted apopinene d e r i v a t i v e s . Trans-4-bromoapopinene (137) was successfully converted by th i s method to ketoester 138 which i s a key intermediate 112 xn the synthesis of p o l y c y c l i c compounds of type 139. 139 - 4 8 -RESULTS AND DISCUSSION. The aims, at the commencement of t h i s work, were to explore the p o s s i b i l i t y of f u n c t i o n a l i s i n g g-ketoesters at the y carbon atom, and investigate the scope of the reactions of the dianion of g-ketoesters. In p a r t i c u l a r , i t was desired to develop the a l d o l and Claisen reactions of the dianion, as possible synthetic routes to acetogenins. The Reaction of A l k y l l i t h i u m Compounds with Sodio Methyl  Acetoacetate. 8 0 However, a recent report has indicated that the treatment of g-ketoesters vrith excess a l k y l l i t h i u m reagents at elevated temperatures lead to cleavage of the ester f u n c t i o n a l i t y from the molecule r e s u l t i n g i n the formation of ketones. 0 0 R'Li/THF 0 R R K l 140 7 8 Although i t had been c l e a r l y demonstrated that the action of n-butyllithium on the monoanion of methyl \ acetoacetate (131) formed the dianion 132, i t was f e l t advisable to reinvestigate t h i s reaction using other a l k y l l i t h i u m reagents, i n case the reaction of n-butyllithium was f o r t u i t o u s l y anamolous. Hence the monoanion of methyl, acetoacetate was prepared by the reaction of sodium hydride - 4 9 -with the B-ketoester at 0°C and treated with methyllithium. Methyllithium was selected because of i t s known tendency to 81 undergo nucleophilic additions. When sodio methyl acetoacetate (131) was treated with one equivalent of methyllithium the dianion 132 was formed, as evidenced by i t s subsequent a l k y l a t i o n with 3-chloropropene. The product from t h i s a l k y l a t i o n was shown to be methyl 3-oxohept-6-enoate (142) by glpc comparison with authentic m a t e r i a l , but the y i e l d of the alkylated ketoester 142 was s l i g h t l y lower than ' 7 8 that obtained using n-butyllithium. No evidence for addition products of methyllithium to the ketoester could be detected by glp c , and hence the lower y i e l d was ascribed to the technical d i f f i c u l t y of handling the more reactive methyllithium. 0 0 1) leq. Me Li 0 0 ^ ^ O C H g 2) CH2CHCH2Cl ^ ^>^^^'0CH3 ( 3 4 ) 131 142 However, addition of more than one equivalent of methyllithium to 131 did r e s u l t i n nucleophilic attack on the carbonyl of the ester. When two equivalents of methyllithium were allowed to react with 131 for a s l i g h t l y longer period of time (30 min) than usually allowed during a l k y l a t i o n reactions (10 min), and the reaction quenched with a c i d , the major product was found to be pentane-2,4-dione (5_) contaminated with some methyl acetoacetate and diacetone -50-alcohol (143). The r e l a t i v e amounts of the products were determined by glpc analysis, using commerically avai l a b l e pentane-2,4-dione and diacetone alcohol as standards, to be 90:5:5 for 5:16:143 respectively. o o 2) H30* O C H 3 1 3 ~ : 1 ) 2 e q . M e L l ( 3 5 ) 0 OH H 3 The presence of pentane-2,4-dione was further demonstrated by treatment of the crude product mixture with a solution of 2,4-dinitrophenylhydrazine and i s o l a t i n g , by c r y s t a l l i s a t i o n , the r e s u l t i n g hydrazone. The s o l i d from t h i s d e r i v a t i s a t i o n reaction had a melting point of 207 -8 2 209°C which i s i n good agreement with the l i t e r a t u r e value of 209°C for the melting point of the 2,4-dinitrophenylhydrazone of pentane-2,4-dione, Furthermore, a mixed melting point of t h i s material with a sample of the hydrazone of authentic pentane-2,4-dione showed no depression. The y i e l d of ~ , pentane-2,4-dione, based on i t s d e r i v a t i v e , was 80%, i n d i c a t i n g that most of the s t a r t i n g material was accounted f o r . S i m i l a r l y , when a larger excess (3 equivalents) of methyllithium was added to sodio methyl acetoacetate (131) -51-and the reaction quenched, the major product was found to be diacetone alcohol (143) with only a l i t t l e pentanedione 5_ and less than 0.1% (the minimum l i m i t of detection) methyl acetoacetate present. The r a t i o of the products was found to be 96:4 (143:5), by glpc, and the y i e l d of the diacetone alcohol, i s o l a t e d as i t s 2,4-dinitrophenylhydrazone, was 82%. The melting point of t h i s derivative was 201-203°C 8 2 ( l i t e r a t u r e mp 203°C), and a mixed melting point with the 2,4-dinitrophenylhydrazone of authentic diacetone alcohol showed no depression. When an even larger excess of methyllithium (6 equivalents) was employed, the reaction products showed no detectable pentane-2,4-dione or methyl acetoacetate but the y i e l d of diacetone alcohol, again i s o l a t e d as i t s hydrazpne, was subst a n t i a l l y lower (44%). Since glpc analysis of the crude reaction mixture f a i l e d to show s i g n i f i c a n t amounts of any product other than the diacetone alcohol, the low y i e l d could be explained by further nucleophilic attack of the methyllithium on the hydroxyketone 143 followed by fragmentation of the re s u l t i n g d i o l . The r e s u l t s of these experiments and others performed 52 78 in our laboratory, ' indicate that the addition of the f i r s t equivalent of an a l k y l l i t h i u m to the sodium s a l t of acetoacetic esters does indeed abstract a proton from the y carbon atom, whilst the second and t h i r d equivalents appear to attack the ester f u n c t i o n a l i t y to give a diketone and a hydroxyketone respectively. The generality of t h i s procedure -52-as a synthetic method of preparing (3-diketones and 8,3-dialkyl 6-hydroxyketones has yet to be investigated. However, addition of a l k y l l i t h i u m i n excess of three equivalents should be avoided, not only because of possible decomposition of the hydroxyketone, but excess a l k y l l i t h i u m reagents have 8 3 been reported to cleave ether solvents of the type used i n these reactions. These r e s u l t s are also i n agreement with the 7 5 reported conversion of g-ketoester 126 to 127, and are not 8 0 i n dissent with those of Spencer. r ^ T ^ f 0 ,) NaH 126 127 It was also f e l t that the generality of t h i s method (sodium hydride - n-butyllithium) of generating the dianion would be enhanced i f i t could be shown to be applicable to c y c l i c g-ketoesters. Analogous dianions Have been formed from c y c l i c B-diketones and g-ketoaldehydes by Hauser,^'35b using amide bases i n l i q u i d ammonia. A l k y l a t i o n of the > dianion derived from 2-acetylcyclohexanone (144, R=CH3) was shown to occur at the exocyclic methyl group, whilst for the ketoaldehyde 144, R=H a l k y l a t i o n was observed at the C 3 • position of the cyclohexane r i n g . , - 5 3 -144 H5 Accordingly, methyl 2-oxocyclohexanecarboxylate (145) 8 4 was prepared i n an analogous manner to the method of Rhoads, and reacted sequentially with sodium hydride, n-butyllithium and 3-chloropropene. The product, i s o l a t e d i n 67% y i e l d , was shown to be homogeneous by glpc and t i c a n a l y s i s , and exhibited spectral properties consistent with the expected product, ; methyl 2-oxo-3-(prop-2-enyl)-cyclohexanecarboxylate (146). Elemental analysis of t h i s product was i n agreement with the proposed structure, as was the molecular weight derived from the low resolution mass spectrum. Further evidence for the presence i n the product of an a l l y l group were the c h a r a c t e r i s t i c absorptions i n the nmr spectrum, centered at 65.75 and 64.93 ppm, t y p i c a l of the v i n y l protons 8 6 of an a l l y l group. The i r spectrum showed the product to exist as a mixture of enol and keto forms i n chloroform so l u t i o n . It would be un l i k e l y that the product a r i s i n g from a-alkylation (alkylation at C1 of the cyclohexane r i n g ) , 147, would exist i n the enol form to any substantial degree. The presence of an absorption i n the i r spectrum at 1650 cm- 1, which would a r i s e from an a,3-unsaturated carbonyl -54-f u n c t i o n a l i t y , such as the ester carbonyl of enol 146b, 8 7 excludes the p o s s i b i l i t y of a-alkylation. 0 C 0 2 C H 3 OH j | ^ s ^ ^ / C O C H 3 146a 146b Nor could the product be derived from a l k y l a t i o n upon oxygen, as there was an absorption, c h a r a c t e r i s t i c of a saturated ketone, at 1715 cm"1 i n the i r spectrum of the product, and the nmr spectrum contained an absorption at 614.23 ppm, a r i s i n g from an enol hydrogen atom. Neither of these absorptions would be observed i f O-alkylation had occurred. It i s highly u n l i k e l y that a l k y l a t i o n would take place at C 4, C 5 or C 6, and the products a r i s i n g from these p o s s i b i l i t i e s were excluded on the basis of an analysis of t h e i r probable nmr and mass spectra. 8 8 The reported major fragmentation pathway of cyclohexanones involves a-cleavage, followed by proton - 5 5 -transfer from Ci to C 3 , loss of C3 as a r a d i c a l , and loss of Ci+ and C5 as a neutral ethylene moiety, for example scheme XIII. Scheme XIII H 8 1 4 6 d This fragmentation pathway would only give a peak at 123 —, the base peak i n the mass spectrum of the product, i f the a l l y l group was on C 3, C 4 or C 5. The C 6 alkylated product would be expected to show a base peak at 163 and the product from the reaction shows no s i g n i f i c a n t peak at t h i s mass/charge value. The nmr spectrum of the product i s only consistent with a f u l l y enolised 3-ketoester i n which a l k y l a t i o n occurred 35b at C 3, and t h i s i s consistent with the r e s u l t s of Hauser for c y c l i c g-ketcaldehydes, and the r e s u l t s obtained i n our -56-78 laboratory with a c y c l i c g-ketoesters. Aldol Reactions of the Dianion of g-Ketoesters. One of the i n i t i a l aims i n developing the sodium hydride - n-butyllithium method of generating the dianion of g-ketoesters was to f u n c t i o n a l i s e the y carbon atom, and i n accordance with t h i s i n i t i a l aim an i n v e s t i g a t i o n of the a l d o l condensation of these dianions was i n i t i a t e d . It was found that the dianion of methyl acetoacetate (132) reacted r a p i d l y with a wide v a r i e t y of aldehydes and ketones to give, as the only product, 6-hydroxy-g-ketoesters 150, equation 36. The r e s u l t s of t h i s i n v e s t i g a t i o n are summarised i n Table V I I . 0 0 0 OH 0 0 -JVM-0CH3 + R R' — R t - ^ O C H 3 C 3 6 ) 132 149 K 150 A l l the products from these a l d o l condensations showed spectral properties i n accord with t h e i r assigned structures, and i n view of the s i m i l a r i t y between these products, the s t r u c t u r a l assignment w i l l not be discussed i n d e t a i l for each i n d i v i d u a l compound. The reactions summarised i n Table VII may be divided into two broad cl a s s e s ; the condensations of a l i p h a t i c aldehydes and ketones, and those of the aromatic aldehydes and ketones. The evidence - 5 7 -for the s t r u c t u r a l assignment of one representative product from each of these classes w i l l be presented i n d e t a i l , and the conclusions applied to the other members of the c l a s s . The a l d o l condensation of propanal with dianion 132 i s t y p i c a l of the reactions of the a l i p h a t i c aldehydes and ketones, i n that i t gave a single d i s t i l l a b l e product. This product was found to be homogeneous by glpc and t i c a n a l y s i s , and elemental analysis of the d i s t i l l e d material was i n agreement with the proposed structure 150b, R'=C2H5, R"=H. The molecular weight, determined by mass spectroscopy, , indicated the product was a one to one adduct of the aldehyde and ketoester. The i r spectrum of the product showed absorptions at 2500, 1740 and 1705 cm-1 indicating the presence i n the molecule of a hydroxyl, a saturated ester and 8 7 a saturated ketone r e s p e c t i v e l y . Evidence that the condensation had occurred at the y carbon atom was manifest i n the nmr spectrum of the product, which showed an absorption at 6 3.52 ppm i n the form of a s i n g l e t , the inte g r a l value of which corresponded to two protons. This absorption was assigned to the methylene group at C 2 of 150b, by analogy to the nmr spectrum of methyl acetoacetate. (The l a t t e r compound shows only three signals i n the nmr spectrum; 63.74 (s, 3H, OCH3), 3.48 (s, 2H, CH2) and 2.27 ppm (s, 3H, CCH3).) The absence of a three proton singlet at ca. 6 2.3 ppm i n the nmr spectrum of the product was further evidence that the condensation had occurred at the y carbon atom. -58-With some of the aromatic aldehydes and ketones, d i f f i c u l t y was encountered when attempts were made to p u r i f y the products by d i s t i l l a t i o n . These products, 150e, f_, g_, m and n, were a l l l i q u i d s and they decomposed to some extent on d i s t i l l a t i o n , and consequently were not obtained i n s u f f i c i e n t purity for elemental a n a l y s i s . These compounds were iso l a t e d by t i c or column chromatography, and t h e i r molecular formulae were determined by high resolution mass spectrometry. In addition to t h e i r spectral properties being i n accord with t h e i r proposed structures, they were converted to t h e i r t r i m e t h y l s i l y l ether d e r i v a t i v e s , and the spectral properties and composition of these derivatives scr u t i n i s e d for consistency with the proposed structure. Methyl 5-hydroxy-,5- (2-methoxyphenyl) -3-oxohexanoate (150n, R'=2-CH3OC6Hi+, R"=CH3) i s representative of these thermally unstable products. The molecular formula of the product was established as CmHigOs by high resolution mass spectroscopy. The presence of the aromatic rin g i n the ! compound was demonstrated by bands i n the i r spectrum of the product at ca. 1600 cm- 1, an absorption i n the uv spectrum i n 89 the region of 270 nm and a complex absorption i n the nmr spectrum centred at 6 7.2 ppm, a l l of which are c h a r a c t e r i s t i c of a 2-methoxyphenyl r i n g . -59-Table VII. Aldol Reactions of Sodio L i t h i o Methyl Acetoacetate i n Tetrahydrofuran OCH-132 0 149 OH 0 0 150 OCH. ( 3 5 ) Product 150 i d e n t i f i c a t i o n l e t t e r R Yield(%) a CH 3 H 26 b CH 3 C H 2 H 73 c CH 3(CH 2 ) 2 ^ ^ 2 H 36 d (CH3) 3C H 82 e C 6 H 5 H 89 f o-CH 3OG 6H 4 H 73 a 2,3- (CH 30) 2C 6H 3 H 68 h 2-Furyl H 68 i CH 3 CH 3 70 i CH 3CH 2 CH 3 56 k - ( C H 2 ) 5 - 63 1 -(CH 2) 4 - 25 m CH 3 77 n O-CH30C6Hlt CH 3 79 E C 6H 5 C 6 H 5 93 -60-The absorptions at 3500, 1740 and 1705 cm"1 i n the i r spectrum of the product indicated, as previously the presence of hydroxyl, saturated ester and ketone f u n c t i o n a l i t i e s i n the molecule. The absence of an absorption at ca. 6 2.3 ppm i n the nmr spectrum of the product was taken as evidence for the aldo l condensation to have occurred at the y p o s i t i o n . The expected two proton s i n g l e t at ca. 6 3.5 ppm for the protons on C 2 of the proposed product was not observed i n the nmr spectrum, and i n i t i a l l y , t h i s absence caused a l i t t l e concern.' There was, however, a multiplet absorption centred at 6 3.1 ppm and another multi p l e t at 6 2.0 ppm, together these absorptions accounted for four protons. It was then r e a l i s e d that during the ald o l condensation, with ketones 149 where R'^R", and with a l l aldehydes, a c h i r a l carbon atom (C 5) i s introduced into the molecule. Since there no longer exists a plane of symmetry i n the molecule (150, R'^R"), the two protons on Ck are no longer magnetically equivalent but are diastereotopic, and consequently the spin-spin s p l i t t i n g between them w i l l become observable i n the nmr spectrum. (Similarly, the protons on C 2 are diastereotopic.) It i s inter e s t i n g to note that the mere presence of a c h i r a l atom at C 5 i s not s u f f i c i e n t for the s p l i t t i n g of the methylene protons at C 2 and to become observable. There must also be a considerable amount of s t e r i c crowding at C 5 for the assymetric environment to extend as far as C 2. Thus i n the products derived from the aldehydes, no spin-spin s p l i t t i n g i s observed for the protons on C 2 (the s p l i t t i n g of the protons at C14 i s due to the presence of the proton on C 5 ) . S i m i l a r l y for the one compound derived from an a l i p h a t i c ketone, with a c h i r a l centre at C 5 no s p l i t t i n g i s observed for the protons at either C 2 or C^. Only with the products derived from the aromatic ketones, and t h e i r s i l y l d e r i v a t i v e s , do the protons at both C 2 and show spin-spin s p l i t t i n g . 88a Similar long range e f f e c t s of aromatic rings are well known. The t r i m e t h y l s i l y l ether of the product from the reaction of o-methoxyacetophenone (149, R' =o-CH3OC6Hlt, R=fCH3) 91 and dianion 132 was prepared by the method of Sweeley. OH 0 0 Me3SiCl _ (CH3)3SI0 0 0 >-^ >^ A)CH3 (ME3SI)2NH - R^ -^-ADCH3 (37) 150 151 This d e r i v a t i v e , as were a l l the t r i m e t h y l s i l y l ethers, was a c o l o u r l e s s , d i s t i l l a b l e l i q u i d , the homogeneity of which was checked by glpc and t i c a n a l y s i s . Elemental analysis was i n agreement with the proposed structure (157n, R'= o-CHgOCgH^, R"=CH3), and the molecular weight confirmed by mass spectroscopy. The major spectral changes accompanying t h i s d e r i v a t i s a t i o n , were the expected ones; loss of the band at 3500 cm"1 i n the i r spectrum, accompanied by the appearance of a band at 1075 cm."1, t h i s l a t t e r band being assigned to the t r i m e t h y l s i l y l : ether f u n c t i o n a l i t y . The presence of a s i n g l e t at 60.0 ppm i n the nmr of spectrum and the loss of the absorption at 64.10 ppm Table VIII. M u l t i p l i c i t y of the nmr Absorptions of the a and y Protons of  some Substituted 6-Hydroxy-3-Ketoesters. H a H a H b H b 150, X=0H 151. X = O S i ( C H 3 ) 3 Compound M u l t i p l i c i t y of Proton I d e n t i f i c a t i o n R l R I ( Resonance X=OH, X=OSi(CH 3) 3 X=OH X=OSi(CH 3) 3 H a H b H a H. 150a CH3 H d s -150b C H , C K 2 H ml s - ' -150c CH 3 ( C H 2 ) 2 H mi s - -150d (CH 3) 3C H ml s - -150e, 151e H ml s m s 150f, 151f O-CH^OCgH^ H ml s m s 150g, 151g 2,4-(CH 30) 2C 6H 3 H mi s m s 150h Fur y l H mi s m s 150j CH 3 C H 2 CH 3 s s s s 150m, 151m C 6H 5 •. CH3 m s m m 150n, 151n O-CH30C6H4 CH 3 m m m m Note: Abbreviations for m u l t i p l i c i t y , m=multiplet, s=singlet, d=doublet 1) M u l t i p l i c i t y i s not just due to proton on C 5, s p l i t t i n g pattern i s of form a r i s i n g from ABX type three nuclei system^O -63-further confirmed the conversion of the alcohol to the t r i m e t h y l s i l y l ether. The remaining absorptions i n the i r and nmr spectra of t h i s derivative were e s s e n t i a l l y unchanged from those i n the o r i g i n a l reaction product. As a check to ensure no molecular rearrangement had occurred on d e r i v a t i s a t i o n (none was apparent from a comparison of the spectra of 150n and 151n), the t r i m e t h y l s i l y l ether was subjected to hydrolysis i n r e f l u x i n g methanol, and the r e s u l t i n g alcohol compared with the o r i g i n a l reaction product. These two compounds appeared i d e n t i c a l i n a l l respects (superimposible i r and nmr spectra and i d e n t i c a l R^  i n two t i c systems). Consequently, i t was. f e l t that the structure of the product from the. a l d o l ' i condensation was firmly established as 150n (R'=o-CH 3OC 6Hi +, R"=CH3). No d i f f i c u l t y was encountered during i s o l a t i o n and p u r i f i c a t i o n of the products from the attempted a l d o l condensation of sodio l i t h i o methyl acetoacetate (132) with 2-furfuraldehyde and benzophenone. The product from the former reaction was a d i s t i l l a b l e l i q u i d , and the l a t t e r a c r y s t a l l i n e s o l i d . The s i g n i f i c a n t spectral properties of these compounds were similar to those outlined for 150n, and elemental analysis and molecular weight determinations being in accord, the products were assigned structures 150h and 150p respectively. From the r e s u l t s i n Table VII, i t i s apparent that the sodium hydride - n-butyllithium procedure of generating the dianion 132 i s applicable to the a l d o l reaction, and gives -64-<5-hydroxy-g-ketoesters i n reasonable y i e l d . The y i e l d i s low f o r products 150 a, c and 1_, and t h i s i s probably due to proton t r a n s f e r from the aldehyde or ketone to the d i a n i o n , as much methyl a c e t o a c e t a t e i s recovered i n these r e a c t i o n s . (The y i e l d s i n Tab l e V I I do not a l l o w f o r t h i s recovery.) I t i s b e l i e v e d t h a t these y i e l d s c o u l d be i n c r e a s e d by v a r i a t i o n o f the r e a c t i o n c o n d i t i o n s , as no s i g n i f i c a n t e f f o r t has been expended t o op t i m i s e the y i e l d s . S i m i l a r d i f f i c u l t i e s i n v o l v i n g proton 3 1 3 2 t r a n s f e r have been r e p o r t e d by Hauser ' d u r i n g the a l d o l condensation of g-diketones. (This work has a l r e a d y been d i s c u s s e d i n p a r t II.) I t i s p o s s i b l e , by analogy to the work of Hauser, t h a t the use of d i l i t h i o s a l t s would i n c r e a s e the y i e l d s of these r e a c t i o n s . In order to make a more d i r e c t comparison w i t h the amide - l i q u i d ammonia c o n d i t i o n s , the d i a n i o n of e t h y l * a c e t o a c e t a t e was prepared employing sodium h y d r i d e and j n - b u t y l l i t h i u m , and condensed w i t h benzophenone. The product, i s o l a t e d i n 81% y i e l d , e x h i b i t e d s p e c t r a l p r o p e r t i e s i n accord w i t h the expected s t r u c t u r e , e t h y l 5-hydroxy-3-oxo-5,5-diphenylpentanoate (152), and had a m e l t i n g p o i n t of 68 - 69°C, which agrees c l o s e l y w i t h the .. l i t e r a t u r e 2 3 v a l u e of 68.5 - 69.5°C f o r 152. A comparison 23 of the y i e l d o b t ained by Hauser, 50%, to the above v a l u e i n d i c a t e s the s u p e r i o r i t y of the sodium h y d r i d e - n - b u t y l l i t h i u m procedure. -65-A b r i e f study of the temperature dependence of the al d o l condensation was made, employing the reaction of propanal with sodio l i t h i o methyl acetoacetate (132) as a model. At temperatures below 0°C, the reaction became very sluggish, and at -78°C only 11% of the desired product was obtained, and much methyl acetoacetate and propanal were recovered. At temperatures higher than 0°C, the y i e l d also decreased, and at 25°C, the product was only i s o l a t e d i n 53% y i e l d , and very l i t t l e propanal was recovered. Presumably, at lower temperatures the rate of the a l d o l reaction slows s u f f i c i e n t l y for proton transfer to become a major competing reaction, whilst at the higher temperature, the rate of self-condensation of the aldehyde becomes s i g n i f i c a n t . Attempts to make use of some of the newer non-nucleophilic bases (discussed i n part III) had only minor success. When the d i l i t h i o s a l t of methyl acetoacetate was generated using two equivalents of li t h i u m diisopropylamide (93), the base having been produced i n s i t u by p r i o r reaction of diisopropylamine and n-butyllithium, and condensed with propanal, a slightly lower y i e l d (62%) of the 6-hydroxy-g-ketoester 150b was obtained. Whilst use of lithium b i s - ( t r i m e t h y l s i l y l ) a m i d e (97) did not appear to generate the dianion. No evidence of any product was obtained from an attempted a l d o l condensation of methyl acetoacetate and propanal when t h i s base (97) was employed. At f i r s t t h i s f a i l u r e was attr i b u t e d to the p o s s i b i l i t y that the base had not been generated, but analysis of t h i s base, prepared by -66-92 the method of Shaw, by means of an acid-base t i t r a t i o n indicated i t to be e s s e n t i a l l y pure. A d d i t i o n a l l y , the b o i l i n g point of the pure base was very similar to the l i t e r a t u r e value, and i n tetrahydrofuran s o l u t i o n , the base gave a purple colouration with 2,2-bipyridyl, which i s 93 i n d i c a t i v e of the amide bases. When 2,2-bipyridyl was employed as an indicator i n the ald o l r e a c t i o n , the solution remained coloured throughout the reaction period, implying that there was s t i l l lithium amide present. From these r e s u l t s i t was presumed that lithium b i s - ( t r i m e t h y l s i l y l ) a m i d e was not a s u f f i c i e n t l y strong base to completely form the dianion. The lower b a s i c i t y of lithium b i s - ( t r i m e t h y l s i l y l ) a m i d e as compared to other lithium dialkylamides i s not exceptional; similar lower b a s i c i t y for silylamines, as compared to t h e i r 113 i s o s t r u c t u r a l alkylamines, has been reported. For example, t r i s i l y l a m i n e exhibits no basic properties, whilst trimethylamine i s a strong base. The lower b a s i c i t y of these silylamines has been postulated to a r i s e from the d e l o c a l i s a t i o n of the lone pair of electrons of the nitrogen atom onto the s i l i c o n atoms, v i a d-rr - p i r bonding. A similar reason could be invoked to account for the apparent low base strength of lithium b i s - ( t r i m e t h y l s i l y l ) a m i d e . It was also desired to investigate the p o s s i b i l i t y of converting the a l d o l products, for example 150, to unsaturated ketoesters. Accordingly, attempts were made employing the usual methods of dehydrating B-ketols. Phosphorus oxychloride i n pyridine, p_-toluenesulfonic acid i n refluxing benzene and -67-reflux i n g sulphuric acid (10% aqueous solution) were a l l t r i e d , but these reagents led to complex mixtures of products. Eventually i t was found that treatment of a l d o l product 150n with anhydrous hydrogen chloride i n chloroform gave smooth conversion to,the unsaturated ketoester 152. (38) The formula of the product of t h i s acid treatment was established by high resolution mass spectroscopy as c l u K i 6 ° u • T n e presence, i n the i r spectrum of the product, of bands at 174 0 and 168 0 cm"1 implied that the molecule contained a saturated ester and an a,g-unsaturated ketone f u n c t i o n a l i t y . This data, coupled with the disappearance of the absorption at 3500 cm - 1 of the s t a r t i n g material suggested strongly that the desired transformation had occurred. Confirmation of the structure of the product was supplied by the presence i n the nmr spectrum of absorptions at 6 6.20 and 6.10 ppm i n d i c a t i v e of v i n y l protons. The signal due to the methyl group on C 5 of the s t a r t i n g material also changed, from a sharp si n g l e t to two doublets which appeared at 6 2.43 and 2.12 ppm and were consistent with those a r i s i n g from v i n y l methyl groups. From a comparison of the nmr spectra of other styrenes (Table IX) and from the Pascual a d d i t i v i t y r u l e , i t i s apparent that i n styrenes a proton which i s c i s to the aromatic r i n g appears at lower f i e l d i n the nmr spectrum than a proton which i s trans to the aromatic r i n g . Accordingly, the signal at 66.20 ppm was assigned to the v i n y l proton of the E isomer of 152, and hence the isomer r a t i o of the product was found to be 2.3:1, E:Z. Table IX. The Chemical S h i f t s of the g-Protons of Some Substituted Styrenes Ry ^Ha C6H5 c 6 R R' H5 Hb 195a 195b Compound R R' Chemical S h i f t of H a Kb 195 H H 5.05 5.55 195 CH3 H 5.08 5.28 195a CH3 CH3 5.85 -195b CH3 CH3 - 6.15 Note: The chemical s h i f t s are of solutions i n carbon t e t r a c h l o r i d e extrapolated to i n f i n i t e d i l u t i o n and are given i n ppm on the 6 s c a l e , r e l a t i v e to TMS.90 The ready thermal decomposition of most of the a l d o l products derived from aromatic aldehydes and ketones was, for some time, a subject of concern. Examination of the l i t e r a t u r e , however, showed several s i m i l a r examples of the 63 94 i n s t a b i l i t y of a l d o l products. ' Tetrasubstituted a l d o l products, for example 154, have been reported to undergo a r e t r o - a l d o l reaction on heating, and i n the presence of a c i d , 6 3 lose water and carbon dioxide to give alkene 157. Scheme XIV 0 R R 155 ^ > - C 0 2 H 156 R R" H0-R' Rm 154 C0 2 H H V A R W R " 157 -70-Less s t e r i c a l l y crowded a l d o l products, for example g-ketol 158, have also been reported as undergoing a s i m i l a r r e t r o - a l d o l r e a c t i o n . P a r t i c u l a r l y prone to decomposition are those g-hydroxy carbonyl compounds which also have a 94a g-aromatic substituent. OH 0 C 6 H 5 158 0 X C 6 H 5 H 159 0 160 (39) An in v e s t i g a t i o n of the decomposition products of one of the a l d o l products 150n, showed that both a r e t r o - a l d o l reaction and a dehydration - decarboxymethylation were occurring. OH 0 0 f T V ^ ^ ^ O C H . ^ ^ O C H -'3 150n 162 ( 4 0 ) -71-D i s t i l l a t i o n of 150n under high vacuum gave a colourless d i s t i l l a t e , which was shown to be a mixture of three components by glpc analysis. The three components were i d e n t i f i e d as o-methoxyacetophenone and the two isomers of 4-(2-methoxyphenyl)-pent-3-en-2-one (162). The f i r s t component was i d e n t i f i e d as 161 by comparison of i t s i r and nmr spectra and glpc retention time with authentic o-methoxyacetophenone. In addition, i t s melting 62 point was very close to the l i t e r a t u r e value for that of 161, and the melting point of a mixture of t h i s component with authentic material was not depressed. Indications that the structures of the two other products were very similar was obtained from t h e i r i r and uv spectra; the l a t t e r being i d e n t i c a l and the former d i f f e r i n g only i n the " f i n g e r p r i n t " region. The uv spectra of these compounds featured bands i n the region 272 and 295 nm, i n d i c a t i v e of a mere extended conjugated system than a simple phenyl r i n g . The presence of an absorption at 167 5 cm - 1 i n the i r spectra, i n d i c a t i v e of an a,g-unsaturated ketone, and the absence of a band at ca. 3500 cm"1, suggested dehydration had occurred. The molecular weight, established by mass spectroscopy, was found to be the same for both compounds, and implied the loss of the elements of water and ketene from the s t a r t i n g material 150n. The nmr spectrum of the major of these two components (the other product was not i s o l a t e d i n s u f f i c i e n t amounts to permit i t s nmr spectrum to be recorded) showed the presence of only one _72_ methoxy group, and together with the lack of an ester absorption i n the i r spectrum, t h i s suggested the structure of these compounds to be 162. Elemental analysis of these compounds was consistent with t h i s proposed st r u c t u r e , and a l l other signals i n the nmr spectrum were i n accord with t h i s structure. A d d i t i o n a l l y , the long range coupling of the resonances of the methoxy group and the v i n y l hydrogen i n the nmr spectrum of the major component permitted i t s i d e n t i f i c a t i o n as the isomer. Attempts to condense formaldehyde with the dianion 132 did not lead to any i d e n t i f i a b l e product. A variet y of conditions were employed i n these attempts, but i n a l l of these reactions, only i n t r a c t a b l e tars were obtained. This 7 95 re s u l t i s not unexceptional, as i t has been reported ' that nucleophilic additions to formaldehyde by enolates of carbonyl compounds, such as acetone and ethyl acetoacetate, often lead to polymeric materials. Attempted Michael Reactions of the Dianion of g-Ketoesters. Attempts were also made to add dianion 132 conjugately to a,g-unsaturated ketones i n a Michael type reaction. However, addition of both methyl v i n y l ketone and cyclohex-2-enone to a solution of sodio l i t h i o methyl acetoacetate led only to the a l d o l products 163 and 164 respectively. -73-OH 0 0 0 C H 3 H O J O C H 3 163 164 The presence of a band at ca. 3500 cm"1 i n the i r spectra of both of these products was i n d i c a t i v e of addition to the carbonyl of the unsaturated ketones, rather than the desired Michael reaction. The spectral properties of these products were consistent with t h e i r proposed structures, and these compounds were i d e n t i f i e d by s i m i l a r c r i t e r i a to the a l d o l products 150 previously described. I t has long been known that Michael additions of 96 Grignard reagents are catalysed by copper (I) s a l t s , and more recently, d i a l k y l copper l i t h i u m reagents have been successfully added i n a conjugate manner to a,^-unsaturated 97 ketones. Accordingly, i n an attempt to promote a Michael reaction, anhydrous cuprous iodide was added to a solut i o n of the dianion 132, p r i o r to the addition of cyclohex-2-enone. Although i t i s believed some form of copper - dianion complex was obtained, as evidenced by the d i s s o l u t i o n of the copper s a l t and formation of a brown so l u t i o n , no products a r i s i n g from a Michael reaction were i s o l a t e d . A v a r i e t y of stoichiometries of cuprous iodide to dianion 132 were employed, but a l l these reactions gave negative r e s u l t s . Since i t had been reported that the product from Michael reactions could be decomposed i f d i r e c t addition of acid was employed i n the work-up of the reaction, the cuprous iodide reaction was repeated and quenched by an inverse procedure i n which the reaction mixture was added to d i l u t e acid. (Formerly, concentrated acid had been d i r e c t l y injected into the reaction mixture.) From t h i s procedure a new product was i s o l a t e d , as well as the previously mentioned al d o l product 164. This compound also showed a band i n the i r spectrum at 3500 cm"1, and so could not be a Michael reaction product. The molecular formula of t h i s new compound was established by high r e s o l u t i o n mass spectroscopy as c i i H i 6 ° i + ' t n e same as that of 16 4. The spectral properties of t h i s new compound and 164 were s i m i l a r i n that t h e i r i r spectra indicated the presence of the same functional groups. However, a comparison of these i r spectra showed a s i g n i f i c a n t difference i n the region between 3000 and 4000 cm"1. The "normal" a l d o l product 164, l i k e a l l the previously prepared a l d o l products, showed only one broad absorption due to the hydroxyl f u n c t i o n a l i t y . Presumably because the compound exists e x c l u s i v e l y i n the form i n which the hydroxyl group i s strongly hydrogen bonded to the ketone. The new product showed two bands i n t h i s region, one sharp, assignable to non-hydrogen bonded hydroxyl, and the other broad band due to associated hydroxyl. This evidence suggested that the hydroxyl was no longer i n a p o s i t i o n where strong hydrogen bonding was possible. Inspection of the nmr spectra of t h i s -75_ compound revealed a resonance at 66.67 ppm corresponding to only one hydrogen atom, and no other signals which could be assigned to v i n y l protons. Hence the double bond present i n the molecule must be t r i s u b s t i t u t e d . One f e a s i b l e reaction which would produce such a t r i s u b s t i t u t e d double bond i s the a l l y l i c rearrangement of 164, equation 41. 164 165 The structure of the product 165 from t h i s a l l y l i c rearrangement i s i n accord with a l l of the observed sp e c t r a l properties of the new product, and hence t h i s product was assigned structure 165. An a d d i t i o n a l experiment, i n which the addition of cyclohex-2-enone to sodio l i t h i o methyl acetoacetate was followed by the inverse quenching procedure, established the presence of cuprous iodide was not necessary for the formation of the a l l y l i c a l l y rearranged product. The f a i l u r e of these Michael reactions was a t t r i b u t e d to the high r e a c t i v i t y of the dianion. Although s i m i l a r Michael reactions, for example the addition of dipotassio butane-1,3-dione (30) to methyl cinnamate previously mentioned, do occur, i t has been generally found that the more reactive the 98 nucleophile employed, the le s s conjugate addition i s observed. Claisen Condensations of The Dianion of g-Ketoesters. It was also desired to investigate the p o s s i b i l i t y of acylating the dianion prepared by the sodium hydride -n-butyllithium procedure as a method of preparing t r i c a r b o n y l compounds. It has been previously mentioned that one of the main reasons for the i n t e r e s t i n polycarbonyl compounds i s t h e i r postulated intermediacy i n the biosynthesis of phenolic compounds. As i t i s anticipated that some of the future applications of the acylations of polycarbonyl compounds may be directed towards biogenetic type synthesis of these acetogenins, a b r i e f digression w i l l be made to amplify t h i s connection between polycarbonyl and phenolic compounds. The i n i t i a l report which indicated the polycarbonyl o r i g i n of some phenolic compounds was the observation, by 99 C o l l i e , of the acid catalysed conversion of heptane-2,4 ,6-trione (166) to orci'nol (167) and other dimeric products. (42) It was these observations, l a t e r confirmed by Birch"^^" and 102 Bethel, which led to the formulation of the polyacetate route to phenolic compounds. The major biosynthetic pathway leading to phenolic compounds i s now believed to be the acyl polymalonate route. This pathway has been described i n d e t a i l i n a number of reviews and i s supported by a considerable amount of 103 evidence. The portion of t h i s pathway which i s relevant to the biosynthesis of phenolic compounds i s outlined below, scheme XV. Scheme XV Fatty Acids Propionate From Shikimate Pathway Cinnanic Acid Benzoic Acid I Nicotinic Acid Anthranilic Acid RCOSCoA 172 R C 0 C H 2 C 0 S E nzyme 173 CH3COSC0A 169 i CH 2 COSCoA C ° 2 H 170 CH 2 COSEnzyme COoH 1 171 RC 0 (C H 2 C 0) nC H 2 C 0 S Enz y me 174 The main steps i n t h i s sequence are the conversion of a c e t y l coenzyme A (169) to malonyl coenzyme A (170), which i s e s s e n t i a l l y a carboxylation, followed by repeated condensation of malonyl coenzyme A units on to an a substituted acetyl coenzyme complex (172), the " s t a r t e r " u n i t , and decarboxylation. This r e s u l t s i n the formation of a l i n e a r polyacyl chain (174) which i s then postulated to undergo intramolecular c y c l i s a t i o n to give phenolic compounds. The laboratory synthesis of analogs of the polyacyl intermediate 174, n=2 has developed along two separate l i n e s ; the synthesis of protected carbonyl compounds employed by 104 Money, Scott and coworkers, v and the d i r e c t synthesis of 45 105 polycarbonyl compounds reported by H a r r i s . ' The observations of both of these groups indicate that the conversion of these analogs to phenolic compounds i s p o s s i b l e . The l i t e r a t u r e pertaining to these biogenetic type conversions has recently been reviewed. In the i n i t i a l attempts to acylate sodio l i t h i o methyl acetoacetate, only one half equivalent of acylating agent was employed, since i t was r e a l i s e d that due to the quenching of the dianion by the i n i t i a l product v i a proton transfer (previously discussed i n part I I ) , a larger amount of t h i s reagent would be an excess. It was found that the reaction of dianion 132 with acyl halides was v i o l e n t l y exothermic, and even when performed at very low temperature (- 7 8°C) , the reaction gave a complex mixture of products. Accordingly, less reactive acylating agents were investigated, and i t was found that the reaction of dianion 132 with esters proceeded smoothly at 0°C to give the desired diketoester, equation 43. 0 0 0 *" R^^0CH3 (43) 176 This procedure, although affording a simple synthesis of diketoesters, was not e n t i r e l y s a t i s f a c t o r y , as the y i e l d of the Claisen condensation product, based on the st a r t i n g ketoester were low. For example, condensation of methyl acetate (175, R=CH3, R'=CH3) with dianion 132, gave only 37% conversion of the ketoester. Attempts to overcome t h i s d i f f i c u l t y be employing an additional equivalent of base in the reaction were not successful, as any base strong enough tc form the dianion was also s u f f i c i e n t l y nucleophilic to attack the ester. Even use of the non-nucleophilic bases, lithium diisopropylamide (93) and lithium N-isopropylcyclohexylamide (94), did not obviate t h i s d i f f i c u l t y . In a series of experiments, i n which d i l i t h i o methyl acetoacetate was prepared by the addition of the ketoester 16_ to three equivalents of lithium diisopropylamide, no evidence of reaction was observed from the condensation of methyl acetate and the dianion. Whilst with methyl benzoate, 0 0 0 >WH 3 + RX0 132 175 -80-again using lithium diisopropylamide as base, the major product i s o l a t e d was N,N-diisopropylbenzamide. This l a t t e r compound exhibited spectral properties i n accord with the assigned structure and possessed a melting point that was i n agreement with the l i t e r a t u r e value for diisopropylbenzamide. Similar experiments i n t h i s s e r i e s , using lithium N-isopropylcyclohexylamide were s l i g h t l y more promising, giving small amounts of the desired diketoester, 4 and 8% from the methyl esters of acetic and benzoic acids r e s p e c t i v e l y . However, again with the aromatic est e r , substantial amounts of the corresponding benzamide were obtained. This N-isopropylcyclohexylbenzamide (196) was characterized by i t s unexceptional spectral properties, and by high resolution mass spectroscopy. The formation of these carboxamides i s not without precedent, similar reactions of non-enolisable esters with lithium amides have been reported as a convenient 107 method for the preparation of carboxamides. It was then envisaged that the degree of the conversion of dianion 132 to the diketoester could be r a i s e d , i f , a f t e r the addition of half an equivalent of the e s t e r , the dianion was regenerated by addition of more base before adding further ester. The stoichiometry of the Claisen condensation of dianions, for example 132, demands that three equivalents of base are needed i f complete conversion of the dianion to product i s to be obtained. But, afte r addition of one half equivalent of est e r , only one half of an equivalent of base i s needed to completely regenerate the dianion. Such an ad d i t i o n , of half an equivalent of base, would r a i s e the maximum th e o r e t i c a l y i e l d to 75%, whereupon addition of one quarter of an equivalent of base would regenerate the dianion completely. Whilst i t i s possible that alternate additions of ester and base i n ever decreasing amounts would eventually give complete conversion of the dianion to diketoester, such a procedure would be very tedious and time consuming. It was found that generation of dianion 132, by the sodium hydride - n-butyllithium procedure, followed sequentially by addition of one half equivalent of ester, a second half equivalent of base, and f i n a l l y by a further half equivalent of ester , did give y i e l d s i n excess of 50%. For example, the condensation of methyl acetate with dianion 132 gave a 56% y i e l d of product by t h i s method. It was adventitiously discovered that addition of a f u l l equivalent of base, afte r addition of the f i r s t portion of ester, gave even higher y i e l d s , and the most convenient procedure which provided the maximum conversion was established as: generation of the dianion by the sodium hydride - n-butyllithium procedure, addition of one half equivalent of ester , addition of one f u l l equivalent of n-butyllithium and f i n a l l y , addition of the remaining half equivalent of ester. In t h i s manner i t v/as possible to { condense methyl acetate with methyl acetoacetate to give methyl 3,5-dioxohexanoate (176, R=CH3) i n 71% y i e l d . -82-The product from t h i s reaction was characterised by an elemental analysis which was consistent with the assigned structure. The molecular weight, determined by mass spectroscopy, indicated the product was a monoacylated derivative of methyl acetoacetate, and the i r spectrum of the product exhibited a broad band at 1600 cm - 1 i n d i c a t i v e of the e n d form of a 3-diketone f u n c t i o n a l i t y . The presence i n the nmr spectrum of a two proton s i n g l e t at 63.57 ppm, assignable to a methylene group bearing two carbonyl groups, excluded the p o s s i b i l i t y of the product being derived from a acylation. The remaining signals i n the nmr spectrum were i n accord with the proposed structure and indicated that the compound existed i n solution mainly as the enol form 176x or 176y. O H 0 0 0 O H 0 1 7 6 x 1 7 6 y This procedure was applied to the Claisen condensation of methyl acetoacetate with several other esters and the results of these investigations are summarised below, Table X. -83-Table X. Claisen Condensations of Sodio L i t h i o Methyl Acetoacetate. 0 0 0 - - 0 C H 3 R OR 132 175 Compound I d e n t i f i c a t i o n R R* Y i e l d (%) 176a CH 3 CH 3 71 176b H CH3 69 176c CH 3 C H 2 C H 2 CH .j 67 176c C H 3 C H 2 C H 2 C H 3 C H 2 33 (11) 1 176d C 6 H 5 CH 3 37 (30) 2 176e £-CH 3OC 6H 4 CH 3 42 (29) 2 Note: 1 Y i e l d i n parentheses ref e r s to ethyl 3,5-dioxooctanoate (177) also i s o l a t e d from the reaction. 2 Yields i n parentheses ref e r s to the diketoacids 178, also i s o l a t e d from the reaction. The product 176b a r i s i n g from the Claisen condensation of methyl formate and dianion 132 decomposed on a l l attempts to p u r i f y i t by d i s t i l l a t i o n and was consequently never obtained i n a n a l y t i c a l purity. The molecular formula of t h i s compound was established by high resolution mass spectroscopy, and i t exhibited spectral properties i n accord with i t s 1 -84-assigned structure. A l l other diketoesters were f u l l y characterised employing the c r i t e r i a previously outlined for methyl dioxohexanoate 176a. When the Claisen condensation of dianion 132 with ethyl butanoate was performed, the product i s o l a t e d was a mixture of methyl and ethyl esters of 3,5-dioxooctanoic acid, the l a t t e r a r i s i n g from t r a n s e s t e r i f i c a t i o n during the reaction. The two esters were separable only with d i f f i c u l t y , and to avoid t h i s complication a l l subsequent reactions were performed with methyl esters. It was found that the y i e l d of the diketoesters from the condensation of aromatic esters with dianion 132 were low. Reinvestigation of the crude product from these reactions revealed one additional product i n each reaction. These additional products were soluble i n sodium hydrogen carbonate solution, and t h e i r i r spectra exhibited a very broad absorption i n the region 3500 to 3000 cm - 1. Both of these data were i n d i c a t i v e of carboxylic acids. Both of these additional products, (one from each aromatic ester investigated) were s o l i d s . After r e c r y s t a l l i s a t i o n the product from the reaction of methyl benzoate possessed a melting point 23 very similar to that reported by Hauser for 3,5-dioxo-5-phenylpentanoic acid (178d, R=H). A l l the spectral properties of t h i s product were consistent with the structure 178d. S i m i l a r l y the spectral properties of the product, derived from the reaction of the dianion with methyl p_-anisate -85-(175/ R=CH a0C6Hi+) , were i n accord with the structure 178e, R=0CH3. In addition, elemental analysis and molecular weight determination of t h i s l a t t e r product were also consistent with t h i s structure. 0 0 0 OH 0 0 178 178x A re-examination of the crude reaction products from a l l the above Claisen condensations showed that the formation of diketoacids was a phenomenon produced only when aromatic esters were used. It i s i n t e r e s t i n g to note that from the aroylation of ethyl acetoacetate with methyl benzoate employing sodium hydride i n r e f l u x i n g 1,2-dimethoxyethane, 24 Kauser reports only the i s o l a t i o n of the diketoacid. The mechanism of the hydrolysis, i n both the work of Hauser and that reported here, remains obscure. One i n t e r e s t i n g acylation that has recently been reported i s the condensation of enolate anions of B-ketoesters with very powerful nucleophiles, such as d i -108 and tri - a n i o n s . For example, i t was possible to condense the dianion of 1-phenylbutane-l,3-dione (29) with the monoanion of ethyl benzoylacetate (179) and with the monoanion of ethyl acetoacetate (3) , to produce tetraketones 180 and 181 respectively. , - 8 6 -0 0 C 6H 5 _ 29 0 0 R >r O C 2 H 5 3, R=H 179. R=C6H5 180, R=C6H5 181, R=H (46) Possible mechanisms for t h i s reaction involve either d i r e c t condensation of the monoanion of the ketoester with the dianion, such a reaction would have a considerable e l e c t r o s t a t i c b a r r i e r to overcome, or elimination of ethoxide from the ketoester and condensation of the r e s u l t i n g acylketene with the dianion. This l a t t e r mechanism has considerable support from studies of the hydrolysis of $-ketoesters where evidence of the intermediacy of acylketenes has been found. It has been found that a similar acylation of methyl acetoacetate may be achieved. I f , upon generation of the dianion of methyl acetoacetate, only one half equivalent of n-butyllithium i s added, and the reaction l e f t at room - 8 7 -temperature for a considerable time (five days) before quenching, the methyl acetoacetate undergoes self-condensation and a s i g n i f i c a n t amount of methyl o r s e l l i n a t e (183) i s obtained. The reaction time may be considerably shortened by ra i s i n g the temperature, but as yet the maximum y i e l d obtained i s only 24%. Scheme XVI 0 0 A A 131 OCH< 0 0 A A OCH-132 OCH-182 C 0 2 C H 3 The product was characterised as methyl o r s e l l i n a t e by comparison of i t s i r and nmr spectra with those of an 110 authentic sample, and, i n add i t i o n , a mixed melting -88-point with the authentic material was undepressed. I t was also possible to i s o l a t e the intermediate t r i k e t o e s t e r 182 by quenching the reaction very c a r e f u l l y . The optimum procedure for t h i s quenching process appears to be an inverse addition of the reaction to mixture of phosphate buffer (pH 6.5) and ether. Chromatography permitted the separation of an unstable o i l , whose spectral properties were consistent with t r i k e t o e s t e r 182, but th i s product was not s u f f i c i e n t l y stable to permit elemental analysis, nor did i t show a parent peak i n the mass spectrum corresponding to 182. This compound underwent spontaneous conversion to methyl o r s e l l i n a t e on standing at 0°C for twelve hours. The nmr spectra of a l l the acylated B-ketoesters indicated that they existed, i n solution at l e a s t , with the B-diketone f u n c t i o n a l i t y mainly i n the enol form, i_.e. 176x or 176y, 178x and 182x or 182y. The nmr spectra did not permit d i s t i n c t i o n to be made between the enol forms of type 176x and 176y or 182x and 182y, but i n the products from aromatic esters the enol forms where the enol double bond i s i n conjugation with the aromatic ri n g (176x and 178x) should be substantially favoured over the other possible enol. The enol content of these acylation products i s considerably higher than that of the al d o l products which exi s t mainly i n the keto form (as determined by nmr spectroscopy), and t h i s i s to be expected as i t i s widely known that B~diketones 98a exi s t i n the enol form to a far greater extent than B ~ k e t o e s t e r s • -89-OH 0 0 0 OH 0 . . . . R - ^ ^ 0 C H 3 = R ^ ^ 0 C H 3 176x 176y OH 0 0 ^ 0 OH 0 A r ^ ^ A ) C H 3 - A r ^ ^ O C H , « 5 ) 178x 178y_ OH O O O _ Q QH 0 Q *OCH 3 ^ ^ O C H 3 182x 182Y (47) A l k y l a t i o n of the Dianion of g-Ketoesters with Dihaloalkanes. The a l k y l a t i o n of sodio l i t h i o methyl acetoacetate with dihaloalkanes was also investigated. In such reactions there i s a p o s s i b i l i t y of two products being formed, depending upon the mode of reaction of the i n i t i a l l y formed, halogen containing product 185. This intermediate may either undergo an intramolecular reaction to give a c y c l i c g-ketoester (186), or may alkylate a second molecule of dianion 132, producing a bis-g-ketoester (187), scheme XVII. -.9©-Scheme XVII 0 0 132 O C H 3 + B r - ( C H 2 ) n - B r 184 B r - ( C H 2 ) n , 0 0 185 OCH-s OCH. H 3 C O OCH-It was found that when one equivalent of 1,3-dibromopropane was added to a solution of dianion 132, two products were obtained i n approximately equal amounts. These products could be separated by chromatography, and were i d e n t i f i e d as methyl 2-oxocyclohexanecarboxylate (186a, n=3) and dimethyl 3,9-dioxoundecanedioate (187a, n=3). The former product was characterised by comparison of i t s i r and nmr spectra with those of authentic material, prepared by the ~91~ , 84 method of Rhoads. This product also exhibited i d e n t i c a l values to that of the authentic material on two d i f f e r e n t t i c systems. The second product was characterised as bis-B-ketoester 187a by an elemental analysis which was i n agreement with the proposed structure, and molecular weight determination indicated a two to one adduct of methyl acetoacetate and dibromopropane. A l l other spectral properties of t h i s product were also i n accord with i t s proposed structure. That the r e a c t i v i t y of the dianion of B-ketoesters i s considerably greater than that of the monoanion i s manifest when the rates of a l k y l a t i o n of the two species i s compared. As has been previously mentioned, the monoanion often requires prolonged periods at elevated temperatures for al k y l a t i o n , whilst the same reaction for the dianion i s es s e n t i a l l y instantaneous at 0°C. In view of t h i s difference i n r e a c t i v i t y , formation of the bis-B-ketoester 187 should be favour.ed by an excess of dianion 132 i n the reaction mixture. In fa c t , when only one half equivalent of 1,3-dibromopropane was added to a solution of the dianion, the only product i s o l a t e d i n 77% y i e l d was. the bis-B-ketoester 187a. Conversely, i f the reaction to form the c y c l i c product i s to be favored, a l l excess dianion must be avpided. . There are two procedures which would achieve t h i s end, -92-addition of the dianion to a large excess of a l k y l a t i n g agent or reaction i n very d i l u t e solution. Although i t was found that the addition of a moderately d i l u t e solution of dianion 132 to a large excess (10 equivalents) of 1,3-dibromopropane did give mostly the c y c l i c product, t h i s procedure would not be convenient i f the dihaloalkane was d i f f i c u l t to obtain or cost l y . This procedure also gave low yi e l d s and apparently involved many side reactions. A double d i l u t i o n experiment i n which the i n i t i a l reaction was performed separately from both reagents and the. second c y c l i s a t i o n step, was found to give both reasonable y i e l d , and mainly the desired product. In t h i s way i t was possible to e f f e c t a 68% conversion of methyl acetoacetate to methyl 2-oxocyclohexanecarboxylate. When dibromomethane was employed as the a l k y l a t i n g agent, no evidence for either the c y c l i c product or the bis-3-ketoester was obtained. When one equivalent of dibromomethane was reacted with sodio l i t h i o methyl acetoacetate, much dibromomethane but only a l i t t l e methyl, acetoacetate was recovered. In addition there was a new compound whose spectral properties could not be reconciled with either of the expected products. The i r spectrum of t h i s product showed two carbonyl bands at 1740 and 1680 cm"1 i n the r a t i o of ca. 2:1. There also appeared to be a shoulder at 1735 cm"1 on the more intense band. This compound also exhibited an absorbtion at 228 nm i n the uv spectrum, which together with the band i n the i r spectrum at 1680 cm"1, -93-indicated an a,B-unsaturated ketone. The mass spectrum of t h i s compound showed a parent peak at 226 m/e which i s eighteen mass units lower than that expected for the bis-B-ketoester. This datum suggested that the new compound had arisen from dehydration of the bis-B-ketoester 187, n=l. However, the only structure which would also possess an a,B-unsaturated ketone i s 188. 0 0 rV°o C H3 187,n=1 0 ' C 0 2 C H 3 - C 0 2 C H 3 188 (48) Elemental analysis of t h i s product was consistent with t h i s structure, as was the nmr spectrum. Such c y c l i s a t i o n s of B-ketoesters are not unknown, for instance, a previously employed example, the synthesis of t r i s p o r i c acid 24_ employs a similar c y c l i s a t i o n . I t was subsequently found that 188 could be formed i n good y i e l d (62%) from dibromomethane and dianion 132, i f only one half equivalent of the a l k y l a t i n g agent i s added very slowly to the dianion solution. ' -94~ Scheme X V I I I 23 MeOK / MeOH 0 The g e n e r a l i t y o f a l k y l a t i o n o f d i a n i o n 132 w i t h d i h a l o a l k a n e s as a s i m p l e and e f f i c i e n t method o f s y n t h e s i s i n g b i s - B - k e t o e s t e r s was f u r t h e r demonstrated by t h e r e a c t i o n o f one h a l f e q u i v a l e n t o f 1,10-dibromodecane w i t h s o d i o l i t h i o m e t h y l a c e t o a c e t a t e , w h i c h gave an a l m o s t q u a n t i t a t i v e y i e l d o f d i m e t h y l 3 , 1 6 - d i o x o o c t a d e c a n e d i o a t e 187b, n=10. T h i s l a t t e r compound was f u l l y c h a r a c t e r i s e d by e l e m e n t a l a n a l y s i s and i t s u n e x c e p t i o n a l s p e c t r a l p r o p e r t i e s . R e a c t i o n o f N i t r i l e s w i t h t h e D i a n i o n o f g - K e t o e s t e r s . 114 I t has r e c e n t l y been r e p o r t e d t h a t e t h y l a c e t o a c e t a t e may be condensed a t the y c a r b o n atom w i t h b e n z o n i t r i l e by employing two e q u i v a l e n t s o f sodium amide -95-i n l i q u i d ammonia. The major product from t h i s reaction i s enamine 190, but the reaction i s complicated by nucleophilic attack of the amide ion on the n i t r i l e , and subsequent condensation of the benzamidine so formed with the ketoester to give pyrimidone 192. A minor product also i s o l a t e d from t h i s reaction i s pyridinedione 191, which arises from c y c l i s a t i o n of enamine 190. 2 , 1 8 9 NaNH2/NHg NH2 0 0 OC2H5 1 9 0 0 H 1 9 1 ( 4 9 ) Generation of the dianion of the g-ketoester by the sodium hydride - n-butyllithium procedure should avoid the complication of pyrimidone formation, and since pyridine-2,4-diones are of some sign i f i c a n c e as therapeutic 115 agents (as analgesics ), the reaction of n i t r i l e s with the dianion of methyl acetoacetate was b r i e f l y investigated. -96-It was found that the reaction between dianion 132 and b e n z o n i t r i l e was sluggish, and extended reaction times were necessary to produce reasonable amounts of condensation products. A reaction period of twelve hours at room temperature was found to give a good y i e l d (66%) of methyl 5-amino-3-oxo-5-phenylpent-4-enoate (194a, R=CKH5) and some (29%) pyridinedione 191. 0 0 N H 2 0 0 A A 0 C H 3 + R " C E N * R ^ M ^ 0 C H 3 ( 5 0 ) 132 189'R=C6H5 . V94a. R = C 6 H 5 193 , R = C H 3 194b, R = C H 3 The enamine 194a was i s o l a t e d by chromatography as a pale yellow l i q u i d which was not thermally stable. Attempted d i s t i l l a t i o n of 194a gave quantitative conversion to a c r y s t a l l i n e compound l a t e r i d e n t i f i e d as pyridinedione 191, (the analagous thermal conversion of enamine 190 to 191 114 has been reported by Sugiyama ). Consequently, enamine 194a was not obtained i n a n a l y t i c a l purity. The molecular formula of t h i s compound was established by high resolution mass spectroscopy and characterisation was effected by the spectral properties of 193a, a l l of which were very similar 114 to those reported for i t s ethyl homolog 190. Pyridinedione 191, both that i s o l a t e d from the reaction mixture d i r e c t l y and that derived from the thermolysis of enamine 194a, exhibited a melting point very similar to that reported by Sugiyama, and a d d i t i o n a l l y i t s i r and uv spectra were i n accord with those previously . , 114,116 reported. ' Extension of t h i s reaction to the condensation of a c e t o n i t r i l e with dianion 132 gave i n high y i e l d (86%) the analogous enamine 193b, R=CH3, but no evidence for the formation of the corresponding pyridinedione was observed. Thermal conversion of enamine 193b to a pyridinedione could not be accomplished; the enamine sublimed unchanged, under a variety of p y r o l y t i c conditions. (No attempts were made to perform t h i s conversion by ether means, for example, by base treatment, which converts the analagous enamine 190 114 to the pyridindione .) Enamine 194b was f u l l y characterised, elemental analysis, molecular weight as determined by mass spectroscopy and a l l other spectral properties were i n accord with the proposed structure. Although the re s u l t s of these two experiments are not as promising as desired, they do indicate the p o s s i b i l i t y of synthesising pyridine-2,4-diones v i a the dianion of 3-ketoesters. -98-Summary It would appear, from the r e s u l t s so far obtained, that the sodium hydride - n-butyllithium procedure of generating the dianion represents a more advantageous method of f u n c t i o n a l i s i n g B-ketoesters at the y p o s i t i o n than the a l k a l i amide - l i q u i d ammonia procedure. It appears to be applicable to a wide range of anionic condensations, generally giving at least moderate y i e l d s of the desired product. The i n i t i a l aim of t h i s work, as previously o u t l i n e d , was to investigate the a l d o l and Claisen condensations of the dianion of B-ketoesters, and the r e s u l t s obtained (Tables VII and X) indicate the f e a s i b i l i t y of these two reactions. It i s hoped that the reactions outlined i n t h i s work w i l l be of some synthetic u t i l i t y i n the future. - 9 9 -EXPERIMENTAL. General. Melting points, which were determined on a Kofler hot stage microscope, and b o i l i n g points are uncorrected. A l l i r , uv and nmr spectra v/ere recorded i n solution, the solvent used i s reported i n parentheses at the beginning of each spectrum. The i r spectra were recorded using a Perkin-Elmer model 700 spectrophotometer, and were cal i b r a t e d with the 1601 cm - 1 band of polystyrene. The assignment of each absorption i s indicated i n parentheses after each band. The uv spectra were recorded using either a Unicam model SP 800 or a Carey model 14 spectrophotometer. The molar extinction c o e f f i c i e n t , where applicable, i s reported i n parentheses aft e r each absorption. The 1E'nmr spectra were recorded on either a Varian model T-60 or HA-100 spectrophotometer. The signal positions are reported using the 6 scale with tetramethylsilane as i n t e r n a l standard, except where indicated. The m u l t i p l i c i t y , coupling constants, integrated peak areas and proton assignments are indicated i n parentheses after each signal. The mass spectra were obtained using an Atlas CH-4b mass spectrometer, and high resolution determinations were obtained using an AEI MS-902 mass spectrometer. Both instruments were operated at an io n i s i n g potential of 70 v o l t s . Elemental microanalyses were performed by Mr. Peter Borda, University of B r i t i s h Columbia. -100-Gas l i q u i d p a r t i t i o n chromatography (glpc) was performed using a Varian-Aerograph model 90P3 chromatograph. The columns employed were: column A, 20 f t . x 3/8 i n . column of 10% carbowax on 60-80 mesh Chromosorb W, column B, 5 f t . x 1/4 i n . column of 3% SE 30 on 60-80 mesh Chromosorb W, column C, 5 f t . x 1/4 i n . column of 5% QF-1 on 60-80 mesh Chromosorb W, and, column D, 5 f t . x 1/4 i n . column of 20% DEGS on 60-80 mesh Chromosrob W. The c a r r i e r gas that was employed was helium with a flow rate of 50 ml/min. The s p e c i f i c column used, along with the column temperature are indicated i n parentheses. S i l i c a gel was obtained from E. Merck, and that used f o r column chromatography was the grade f i n e r than 200 mesh ASTM, whilst that used for t h i n layer chromatography (tic) was the grade TPF^^^. Tetrahydrofuran was dried by r e f l u x i n g over l i t h i u m aluminium hydride for a minimum of two hours p r i o r to use. Reaction of A l k y l l i t h i u m s with the Sodium S a l t of g-Ketoesters. Methyl 3-oxohept-6-enoate (142) Sodium hydride, as a 57% mineral o i l d i spersion, (0.465 g, 11.0 mole) was weighed into an oven dried 50 ml f l a s h , and tetrahydrofuran (ca. 25 ml) was d i s t i l l e d d i r e c t l y into t h i s f l a s h , from li t h i u m aluminium hydride. The f l a s k -101-was equipped with a magnetic s t i r r e r , stoppered (septum cap), cooled i n ice and flushed with nitrogen. Methyl aceotacetate (1.161 g, 10.0 mmole) was added dropwise to the cooled s l u r r y , and aft e r the addition was complete, the reaction was allowed to stand for ten minutes. Methyllithium, as a 2 IM soluti o n i n hexane, (5.0 ml, 10.5 mmole) was added dropwise to the reaction and the reaction allowed to stand a further ten minutes afte r t h i s addition. 3-Bromopropene (1.332 g, 11.0 mmole) was added i n one portion to the reaction and af t e r a f i n a l ten minute period, the reaction was quenched with concentrated hydrochloric acid (ca. 2 nil) . The reaction was worked up by the addition of ether (35 ml) and water (5 ml). The aqueous phase was separated, and further extracted with ether (2 x 35 ml). The ethereal extracts were combined, washed with saturated sodium chloride solution (6 x 20 ml), dried over anhydrous sodium sulphate and f i l t e r e d . The solvents were removed by evaporation under reduced pressure, and the r e s u l t i n g o i l d i s t i l l e d to give 1.170 g (75%) of 142, bp 99-101°C (14 mm), ( l i t . 7 8 bp 99-100°C (14 mm)), which had i d e n t i c a l glpc retention times (col. B, 120°C and c o l . D, 140°C) as previously prepared 117 methyl 3-oxohept-6-enoate (142). Methyl 2-oxocyclohexanecarboxylate (145). Sodium hydride, as a 57% mineral o i l dispersion, (0.933 g, 22.0 mmole) was weighed into an over dried 100 ml -102-two-necked f l a s h and, p_-dioxane (ca. 50 ml) was d i s t i l l e d d i r e c t l y into t h i s f l a s k from lithiu m aluminium hydride. The flask was equipped with a magnetic s t i r r e r , a dropping funnel with a nitrogen i n l e t and a re f l u x condenser carrying a calcium chloride drying tube. Dimethyl carbonate (1.803 g, 20.0 mmole) was added to the flask and the assembly flushed with nitrogen. A solution of cyclohexanone (1.963 g, 20.0 mmole) i n p_-dioxane (10 ml) was added dropwise over a period of one hour to the flask and af t e r completion of the addition the fl a s k was heated u n t i l a moderate rate' of r e f l u x was attained and t h i s continued for three hours. The flask was allowed to cool to room temperature and the solvents removed by evaporation under reduced pressure. Ether (50 ml) was then added and the reaction neutralised by the addition of g l a c i a l acetic acid (2 ml), and water (15 ml) added to dissolve the sol i d s produced. The aqueous phase was separated and further extracted with ether (2 x 25 ml). The ethereal extracts were combined, washed with saturated, sodium chloride solution (4 x 20 ml), dried over anhydrous sodium sulphate and f i l t e r e d . The ether was removed by evaporation under reduced pressure, and the r e s u l t i n g o i l d i s t i l l e d under reduced pressure to give 1.269 g (83%) of 145, bp 97-100°C (14 mm)' ( l i t . 8 4 bp 94-95°C (19 mm)). i r (CHC13) 3600 (enol OH), 1745 (ester C=0, keto form), 1720 (C=0), 1650 (ester C=0, enol form) and 1610 cm"1 (C=C, enol form); -103-nmr (CDCL3) 614.3 (broad s, exchangeable D 20, 1, enol OH), 3,76 (s, 3, OCH3) and 2.60 - 1.74 ppm (m, 8, cyclohexyl protons). Methyl 2-OXO-3-(prop-2-enyl)-cyclohexanecarboxylate (146). This compound was prepared by the same procedure as that employed i n the preparation of methyl 3-oxohept-6-enoate (142). The reagents used were: sodium hydride, as a 57% mineral o i l dispersion, (0.075 g, 1.65 mmole), methyl 2-oxocyclohexanecarboxylate (0.233 g, 1.50 mmole) n-butyllithium, as a 2.3M solution i n hexane (0.7 ml, 1.61 mmole) and 3-bromopropene (0.198 g, 1.65 mmole), which gave 0.197 g (67%) of 146, bp 110-112°C (14 mm). ir(CHCl 3) 3600 (enol OH), 1740 (ester C=0, keto form), 1715 (C=0), 1650 (ester C=0, enol form) and 1610 cm - 1 (C=C) ; nmr (CCl^) 614.23 (broad s, exchangeable D 20, 1, enol OH), 6.00-5.50 (m, 1, C=CH) , 5.16-4.86 (m, 2, C=CH2), 3.70 (s, 3, OCH3) and 2.70-1.10 ppm (m, 9, cyclohexyl protons and CH of propenyl group); mass spectrum m/e ( r e l intensity) 196(55), 183(6), 178(9), 165 (37), 164 (60), 155 (24), 154 (51), 137 (36), 136 (49), 125(32), 123 (100), 122 (30), 119 (49), 109 (24), 108 (77), 95 (70), 94 (48), 93 (47), 87 (54), 79 (77), 68 (65), 55(90), and 41(100); analysis calcd. for C 1 1 H 1 6 0 3 : C 67.32, H 8.22: found : C 67.31, H 8.35. -104-Reactlon of Methyllithium with the Sodium Salt of Methyl  Acetoacetate. General Procedure. Sodium hydride, as a 57% mineral o i l dispersion (0.465 g, 11.0 mmoles) was weighed into an oven dried f l a s k and tetrahydrofuran d i s t i l l e d d i r e c t l y into t h i s f l a s k from lithium aluminium hydride. The flask was equipped with a magnetic s t i r r e r , stoppered (septum cap), cooled i n ice and flushed with nitrogen. Methyl acetoacetate (1.161 g, 10.0 mmole) was added dropwise to the cooled s l u r r y , and the reaction allowed to stand for ten minutes afte r the addition was complete. Various quantities of methyllithium were then added and the reaction allowed to stand for t h i r t y minutes before being quenched with a s l i g h t excess of concentrated hydrochloric acid. The reaction was worked up by the addition of ether (35 ml) and water (10 ml). The aqueous phase was separated, saturated with sodium chloride and further extracted with ether ( 2 x 3 5 ml). The ethereal extracts were combined, washed with saturated sodium chloride solution (6 x 20 ml), dried over anhydrous sodium sulphate and f i l t e r e d . The solvents were removed by evaporation under reduced pressure. The r e s u l t i n g o i l s were then subjected to glpc analysis and treated with 2,4-dinitrophenylhydrazine (2.200 g, 11.0 mmole) dissolved i n methanol, a c i d i f i e d with concentrated sulphuric acid, to convert any ketonic compound -105-to i t s 2,4-dinitrophenylhydrazqne. a) With two equivalents of methyllithium. The general procedure was performed using 10 ml of a 2.1M solution of methyllithium i n hexane. The glpc analysis (column D, 140°C) showed the product to contain mainly pentane-2,4-dione with a l i t t l e methyl acetoacetate and diacetone alcohol (rel proportions, 90:5:5). The s o l i d from the d e r i v i t i s a t i o n reaction was washed with ether and r e c r y s t a l l i s e d from ethanol to give 2.301 g (80%) of the 2,4-dinitrophenylhydrazone cf pentane-2,4-dione, mp 2 07 -209°C, mixed mp 207 - 209°C. b) With three equivalents of methyllithium. The general procedure was performed using 15 ml of a 2.1M solution of methyllithium i n hexane. The glpc analysis (column D, 140°C), showed the product to contain mainly diacetone alcohol with only a l i t t l e pentane-2,4-dione present, (rel proportions, 96:4). The s o l i d from the d e r i v a t i s a t i o n reaction was r e c r y s t a l l i s e d from methanol-water (9:1, v/v) to give 2.419 g (82%) of the 2,4-dinitrophenylhydrazone of diacetone alcohol, mp 201 - 203°C mixed mp 201 - 203°C. c) Wtih six equivalents of methyllithium. The general procedure was performed using 35 ml of a 2.1M solution of methyllithium i n hexane. The glpc analysis (column D, 140°C) showed the major product to be diacetone alcohol, with no pentane-2,4-dione or methyl acetoacetate -106-present. However, the s o l i d from the d e r i v a t i s a t i o n reaction was is o l a t e d i n smaller amounts, and af t e r r e c r y s t a l l i s a t i o n from methanol-water (9:1 v/v) only 1.294 g (44%) of the 2,4-dinitrophenylhydrazone of diacetone alcohol, mp 201-203°C, was i s o l a t e d . Aldol Reactions of The Dianion of g-Ketoesters. Methyl 5-hydroxy-5-methyl-3-oxohexanoate (150i) Sodium hydride, as a 57% mineral o i l dispersion, (0.465 g, 11.0 mmole) was weighed into an even-dried 50 ml flask and tetrahydrofuran (ca. 25 ml) was d i s t i l l e d d i r e c t l y into t h i s f lask from lithiu m aluminium hydride. The flask was equipped with a magnetic s t i r r e r , stoppered (septum cap), cooled i n ice to 0°C and flushed with nitrogen. Methyl acetoacetate (1.161 g, 10.0 mmole) was added dropwise to the cooled s l u r r y and the reaction allowed to s t i r for ten minutes after the addition was complete. A solution of n-butyllithium (5 ml 2.1M i n hexane, 10.5 mmole) was added dropwise to the solution and the reaction allowed to s t i r for a further ten minutes. Acetone (0.638 g, 11.0 mmole) was added i n one portion and the reaction allowed to s t i r for ten minutes before being quenched with concentrated hydrochloric acid (ca. 2 ml). The reaction was worked up by the addition of water (10 ml) and d i e t h y l ether (35 ml). The aqueous layer was separated and further extracted with ether (2 x 35' ml). The organic extracts were combined, washed -107-with saturated sodium chloride solution (6 x 15 ml), dried over anhydrous sodium sulphate and f i l t e r e d . The solvents were removed by evaporation under reduced pressure and d i s t i l l a t i o n of the re s u l t i n g o i l gave 1.162 g (72%) of 150i, bp 51-52° (14 mm). i r (CKC13) 3500 (OH), 1740 (ester C=0) and 1705 cm"1 (C=0); nmr (CDC13) 63.76 (s, 3, OCH3) , 3.48 (s, 2, COCH2C02Me), 3.27 (broad s, 1, exchangeable D 20, OH), 2.70 (s, 2, HOCCH2CO) and 1.30 ppm (s, 6, C(CH 3) 2); mass spectrum m/e (rel intensity) 174(4), 159(48), 128 (71), 116 (100), 85 (62), 59 (87) and 43 (87) ; analysis calcd for C s H i i i O ^ C 55.16, H 8.10: found: C 54.97, H 8.32. Methyl 5-hydroxy-5-methyl-3-oxoheptanoate (150j) This compound was prepared by the same procedure as that employed i n the preparation of methyl 5-hydroxy-5-methyl-3-oxohexanoate (150j). The reagents used i n the preparation were: sodium hydride, as a 57% mineral o i l dispersion, (0.467 g, 11.0 mmole), methyl acetoacetate (1.161 g, 10.0 mmole), n-butyllithium, as a 2.1M solution i n hexane, (5 ml, 10.5 mmole) and 3-butanone (0.792 g, 11.0 mmole), which gave 1.052 g (56%) of 150j, bp 88-89° (14 mm). i r (neat film) 3500 (OH), 1740 (ester C=0) and 1705 cm"1 (C=0); -108-nmr (CDC13) 63.77 (s, 3, OCH 3), 3.51 (s, 2, COCH2C02Me), 3.15 (broad s, 1, exchangeable D 20, OH), 2.71 (s, 2, HOCCH2CO), 1.60 (distorted q, 2, J = 8Ez, MeCH2COH), 1.27 (s, 3, CH3COH) and 0.92 ppm (distorted t , 3, J = 8Hz, CH 3CH 2); mass spectrum m/e ( r e l intensity) 188(0.2), 170(10), 159(49), 128 (75), 116 (50), 85 (47), 73 (47) and 43 (100); analysis calcd for CgHjgOij: C 57.43 H 8.57: found : C 57.27 H 8.71 Methyl 4-(1-hydrcxycyclohexyl)-3-oxobutanoate (150k). This compound was also prepared by the same procedure as that employed i n the preparation of methyl 5-hydroxy-5-methyl-3-oxohexanoate (150i). The reagents used i n the preparation v/ere: sodium hydride, as a 57% mineral o i l dispersion, (0.465 g, 11.0 mmole), methyl acetoacetate (1.161 g, 10.0 mmole), n-butyllithium, as a 2.1M solution i n hexane, (5 ml, 10.5 mmole) and cyclohexanone (1.078 g, 11.0 mmole), which gave 1.348 g (63%) of 150k„ bp 95-96° (0.3 mm). i r (neat film) 3500 (OH), 1740 (ester C=0) and 1705 cm"1 (C=0); nmr (CDC13) 63.75 (s, 3, OCH 3), 3.50 (s, 2, COCH2C02Me), 3.11 (broad s, 1, exchangeable D 20, OH), (s, 2, HOCCH2CO) and 1.52 ppm (m, 10, cyclohexyl protons); mass spectrum m/e (rel intensity) 214(3), 196(18), 182(12), 138 (61), 123 (40), 122 (47), 116 (44), 98 (63), 95 (60), 80 (53), 69 (69), 55 (84), and 43 (100); -109-analysis calcd for C^H^O^: C 61.66 H. 8.47 found: C 61.84 H 8.47 Methyl 4-(1-hydroxycyclopentyl)-3-oxobutanoate (1501) This compound was prepared by the same procedure as that employed i n the preparation of methyl 5-hydroxy-5-methyl-3-oxohexanoate (150i). The reagents used i n the preparation were: sodium hydride, as a 57% mineral o i l dispersion, (0.466 g, 11.0 mmole), methyl acetoacetate (1.161 g, 10.0 mmole), n-butyllithium, as a 2.1M solutipn i n hexane, (5 ml, 10.5 mmole) and cyclopentanone (0.924 g, 11.0 mmole), which gave 0.502 g (25%) of 1501, bp 67-68° (0.3 mm). i r (neat film) 3500 (OH), 1740 (ester C=0) and 1705 cm - 1 (C=0); nmr (CDC1 ) 63.77 (s, 3, OCH3) , 3.52 (s, 2, COCH2C02Me), 3.10 (broad s, 1, exchangeable D 20, OH), 2.90 (s, 2, HOCCH2CO) and 1.72 ppm (m, 8, cyclopentyl protons). mass spectrum m/e (rel intensity) 200(4), 182(12), 159(89), 126 (62), 116 (89), 109 (51), 198 (65), 101 (84), 85 (89), 84 (98), 67 (62), 59 (62), 55 (100) and 43 (100); analysis calcd for C i 0H 1 6O t t: C 59.98 H 8.05 found: C 60.14 H 7.94 Methyl 5-hydroxy-3-oxoheptanoate (150b) This compound was prepared by the same procedure as that employed i n the preparation of methyl 5-hydroxy-5-methyl-3-oxohexanoate (150a). The reagents used i n the -110-preparation were: sodium hydride, as a 57% mineral o i l dispersion, (0.465 g, 11.0 mmole), methyl acetoacetate (1.161 g, 10.0 mmole), n-butyllithium, as a 2.1M solution i n hexane, (5.0 ml, 10.5 mmole) and propanal (0.639 g, 11.0 mmole), which gave 1.270 g (73%) of 150b, bp 86-87° (0.5 mm), i r (neat film) 3500 (OH), 1740 (ester C=0) and 1705 cm"1 (C=0); nmr (CDC13) 64.00 (m, 1, CHOH), 3.76 (s, 3, OCH3) , 3.52 (s, 2, COCH2C02Me), 2.66 (m, 2, HOCCH2CO), 2.43 (broad s, 1, exchangeable D 20, OH), 1.45 (m, 2, HOCCH2CH3) and 0.95 ppm. (m, 3, CH 2CH 3) ; mass spectrum m/e ( r e l intensity) 174(1), 156(6), 145(17), 116 (16), 114 (38), 101 (32), 83 (59), 71 (49), 69 (53), 59 (52), and 43(100); analysis calcd for CgH^O^: C 55.16 H 8.10 found: C 54.95 H 8.09 Methyl 5-hydroxy-3-oxononanoate (150c) This compound was prepared by the same procedure as that employed i n the preparation of methyl 5-hydroxy-5-methyl-3-oxohexanoate (150i). The reagents used i n the preparation were: sodium hydride, as a 57% mineral o i l dispersion, (0.465 g, 11.0 mmole), methyl acetoacetate (1.161 g, 10.0 mmole), n-butyllithium, as a 2.1M solution i n hexane, (5 ml, 10.5 mmole) and pentanal (0.946 g, 11.0 mmole), which gave 0.727 g (36%) of 150c, bp 55-56° (0.2 mm). -111-i r (neat film) 3500 (OH), 1740 (ester C=0) and 1705 cm"1 (C=0); nmr (CDC1 ) 64.00 (m. 1. HOCH), 3.76 (s, 3, OCH 3), 3.50 (s, 2, COCH2C02Me), 2.66 (m, 2, HOCCH2CO), 2.42 (broad s, 1, exchangeable D 20, OH) and 1.52-0.77 ppm (m, 9, CH 3CH 2CH 2CH 2COH); mass spectrum m/e (rel intensity) 202) 1), 184 (9), 145 (38), 127 (9), 116 (36), 113 (35), 101(23), 97 (14), 85 (27), 84 (19), 58 (32) and 43 (100) ; analysis calcd for C K J H ^ O ^ : C 59.39 H 8.97 found: C 59.19 H 8.96 Methyl 5-hydroxy-3-oxohexanoate (150a) This compound was prepared by the same procedure as that employed i n the preparation of methyl 5-hydroxy-5-methyl-3-oxohexanoat'e (150i) . The reagents used i n the preparation were: sodium hydride, as a 57% mineral o i l dispersion, (0.465 g, 11.0 mmole), methyl acetoacetate (1.161'g, 10.0 mmole), n-butyllithium, as a 2.1M solution i n hexame, (5 ml, 10.5 mmole), and acetaldehyde (0.484 g, 11.0 mmole), which gave 0.416 g (26%) of 150a, bp 42-43° (0.3 mm), i r (CHC13) 3500 (OH), 1740 (ester C=0) and 1705 cm"1 (C=0); nmr (CClk) 64.10 (m„ 1, CHOH), 3.70 (s, 3, OCH3) (s, 2, COCH2C02Me), 3.00 (broad s, 1, exchangeable D 20, OH), 2.62 (m, 2, HOCCH2CO) and 1.12 ppm (m, 3, CH2COH); -112-mass spectrum m/e ( r e l intensity) 160(40), 142(54), 127 (33), 116 (60), 101 (73), 85(42), 59 (64) and 43 (100); analysis calcd for C7Hi20i+: C 52.49 H 7.55 found: C 52.65 H 7.39 Methyl 5-hydroxy-6,6-dimethyl-3-oxoheptanoate (150d. This compound was prepared by the same procedure as that employed i n the preparation of methyl 5-hydroxy-5-methyl-3-oxohexanoate (150i). The reagents used i n the preparation were: sodium hydride, as a 57% mineral o i l dispersion, (0.465 g, 11.0 mmole), methyl acetoacetate (1.161 g, 10.0 mmole), n-butyllithium, as a 2.1M solution i n hexane, (5 ml, 10.5 mmole), and 2,2-dimethylpropanal (0.946 g, 11.0 mmole), which gave 1.654 g (82%) of 150d, bp 68-69° (0.2 mm). i r (CHCl3) 3500 (O-H), 174 0 (ester C=0) and 1705 cm"1 (C=0); nmr (CC14) 3.70 (s, 3, OCH 3), 3.63 (m, 1, CHOH), 3.42 (s, 2, COCH2C02Me), 3.00 (broad s, 1, exchangeable D 20, OH), 2.58 (m, 2, H0CCH2C0) and 0.87 ppm (s, 9, CH 3) 3C); mass spectrum m/e ( r e l intensity) 202(1), 184(10), 170(22), 155(23), 145(90), 127 (42), 116 (48), 115(48), 113 (92), 111(94), 101 (60), 56 (96), 83 (87), 71 (100), 69 (94), 59 (77), 55(100) and 43 (100); analysis calcd for CxoHieO^: C 59.39 H 8.97 found: C 59.15 H 8. 95 -113-Methyl 5-hydroxy-5-(2-methoxyphenyl)-3-oxohexanoate (150n) Sodium hydride, as a 57% mineral o i l dispersion, ' (0.465 g, 11.0 mmole) was weighted into an oven dried 50 ml f l a s k , and tetrahydrofuran (ca. 25 ml) was d i s t i l l e d d i r e c t l y into t h i s f l a s k from lithium aluminium hydride. The f l a s k was f i t t e d with a magnetic s t i r r e r , stoppered (serum cap), cooled i n i c e to 0° and flushed with nitrogen. Methyl acetoaceate (1.161 g, 10.0 mmole) was added dropwise to the cooled s l u r r y , and a f t e r the addition was complete, the reaction was allowed to s t i r f or ten minutes. A solution of n-butyllithium (5 ml 2.1M i n hexane, 10.5 mmole) was added dropwise to the solution and the reaction allowed to s t i r for a further ten minutes. o-Methoxyacetophenone (1.650 g, 11.0 mmoles) dissolved i n TKF (5 ml) was added i n one portion and the reaction allowed to s t i r f or ten minutes before being quenched with concentrated hydrochloric acid (ca. 2 ml). The reaction was worked up by the addition of water (10 ml) and di e t h y l ether (35 ml). The aqueous layer was separated and further extracted with ether (2 x 35 ml). The ethereal extracts were combined, washed with saturated sodium chloride solution (6 x 15 ml), dried over anhydrous sodium sulphate and f i l t e r e d . The solvents were removed under reduced pressure to give 2. 550 g of pale y e l l o w - o i l . P u r i f i c a t i o n of t h i s o i l was achieved by t i c : crude 150n (544 mg) was chromatographed on a 20 x 20 cm s i l i c a coated plate, adsorbant thickness 0.9 mm, using a mixture of chloroform -114-and ethyl acetate (9:1, v/v) as eluent. After e l u t i o n , the band l y i n g i n the region R f 0.25 - 0.33 was removed and extracted with ether (15 ml). The solvent was removed by evaporation under reduced pressure to give 471 mg (73% extrapolated)* of 150n. i r (CHC13) 3500 (O-H), 1740 (ester C=0) and 1705 cm"1 (C=0); uv (CH3OH) 276, 270 and 264 nm (shoulder); nmr (CC13) 67.70 - 6.70 (m, 4, a r y l protons), 4.10 (broad s, 1, exchangeable D 20, OH), 3.82 (s, 3, ester OCH 3), 3.63 (s, 3, a r y l OCH 3), 3. 33 - 1. 65 (m, 4, CH^COCH^) and 1.50 ppm (s, 3, HOCCH3); mass spectrum: a) high resolution calcd for C 1 [ ( H i 8 05 , 266.1154 amu, found, 266.1135 m/e; b) low resolution m/e (r e l intensity) 266 (10), 251(8), 234(16), 208 (10), 159 (34), 151 (78), 135 (94), 115 (52), 91 (25), 77 (80), 59 (47) and 43 (100). * Note: Extrapolated y i e l d i s calculated by puri f y i n g a small portion of the crude product, and assuming that the remainder of the crude product would y i e l d the same proportion of pure compound. Methyl 5- (2.-methoxyphenyl)-3-oxo-5-trimethylsiloxyhexanoate (151n) Methyl 5-hydroxy-5-(2-methoxyphenyl)-3-oxohexanoate (150n) (0.257 g , 0.99 mmole), chlorotrimethylsilane (0.108 g, 1.00 mmole) and hexamethyldisilazane (0.081 g, 0.50 mmole) were - U n -dissolved i n dry pyridine (ca. 5 ml) and the solution s t i r r e d for ten minutes. A f i n e white p r e c i p i t a t e was thrown down and t h i s was f i l t e r e d o f f and washed with ether (3 x 10 ml). The washings were added to the f i l t r a t e and the solvents removed by evaporation under reduced pressure. The r e s u l t i n g o i l was d i s t i l l e d under high vacuum to give 0.176 g (65%) of 151n, bp 83-85° (0.3 mm). i r (CHC13) 1740 (ester C=0), 1705 (C=0) and 1075 cm"1 (Si-OC); nmr (CCl^, ext TMS) 7.55 - 6.67 (m, 4, a r y l protons), 3.80 (s, 3, ester OCH 3), 3.53 (s, 3, a r y l OCH 3), 3.20 (m, 2, COCH2C02Me), 2.80 (m, 2, ArCCH 2CO), 1.67 (2, 3, CCH3) and 0.00 ppm (s, 9, ( C H 3 ) 3 S i ) ; mass spectrum m/e (rel intensity) 338 (3), 323 (2), 308 (2), 265 (2), 223 (98), 173 (35), 151(19), 135 (80), 115 (17), 105 (46), 91(19), 75(100), 59 (30) , and 43 (76); analysis calcd for C 1 7 H 2 6 0 5 S i : C 60.33 H 7.74 found; C 60.20 H 7.49 Hydrolysis of Methyl 5-(2-methoxyphenyl)-3-oxo-5-trimethyl-siloxyhexanoate (151n) Methyl 5-(2-methoxyphenyl)-3-oxo-5-trimethylsiloxy-hexanoate (151n) (0.170 g, 0.50 mmole) was dissolved i n methanol (10 ml) and the solution heated to r e f l u x . After a period of t h i r t y minutes at reflux the solution was cooled -116-and f i l t e r e d . The methanol was removed by evaporation under reduced pressure and the r e s u l t i n g o i l p u r i f i e d by preparative t i c , using a 20 x 20 cm s i l i c a coated plate, adsorbant thickness 0.5 mm, and employing a mixture of chloroform and ethyl acetate (9:1, v/v) as eluent. The band l y i n g i n the region 0.25 - 0.33 was removed and extracted with ether. The solvent was removed by evaporation under reduced pressure to give 95 mg (71%) of methyl 5-hydroxy-5-(2-methoxyphenyl) 3-oxohexanoate (150n) f which showed i d e n t i c a l i r and nmr spectra to 150n before d e r i v i t i s a t i o n . Methyl 5-(2-methoxyphenyl)-3-oxohex-4-enoate (153) Chloroform (ca. 10 ml) was saturated with anhydrous hydrogen chloride, by d i r e c t passage of the gas through the solvent. Methyl 5-hydroxy-5-(2-methoxyphenyl)-3-oxohexanoate (150n) (0.051 g, 0.19 mmole) was dissolved i n t h i s chloroform and the solution s t i r r e d for 3 0 minutes. The solution was washed with saturated sodium hydrogen carbonate solution ( 4 x 5 ml), and with saturated sodium chloride solution ( 2 x 5 ml), dried over anhydrous sodium sulphate and f i l t e r e d . The chloroform was removed by d i s t i l l a t i o n to give 0.04 0 g (85%) of a mixture of Z_ and E isomers of 153 (ratio of isomers, Z_:E 1.0:2.3, by nmr). i r (CHC13) 1740 (ester C=0), 1680 (C=CC=0) and 1600 cm - 1 (C=C) ; -117-uv (CH3OH) 320 (shoulder) and 278 nm; nmr (CClk) 67.40 - 6.67 (m, 4, a r y l protons), 6.20 (m, 0.7, E - C=CH), 6.10 (m, 0.3, Z - C=CH), 3.82 (s, 3, ester 0CH3) , 3.70 (d, 2.1, J = 1 Hz, E- a r y l OCH 3), 3.60 (d, 0.9, J = 1 Hz, Z- a r y l OCH 3), 3.40 (s, 2, COCH2C02Me), 2.43 (d, 2.1, J = 1 Hz, E- CCH ) and 2.12 ppm (d, 0.9, J = 1 Hz, Z- CCH3); mass spectrum: a) high resolution calcd for C l 4 H l 6 0 4 248.1048 amu, found 248.1064 m/e; b) low resolution m/e (rel intensity) 248 (2), 217 (14), 189 (3), 175 (11), 160 (13), 159 (100), 150(5), 136 (17), 119 (4), 115 (4), 105 (6), 91(9), 77 (4), 69 (2), 59 (2), and 43 (22). Thermolysis of Methyl 5-hydroxy-5-(2-methoxyphenyl)-3-oxohexanoate (150n) Methyl 5-hydroxy-5-(2-methoxyphenyl)-3-oxohexanoate (0.570 g, 2.14 mmole) was heated i n a bulb-to-bulb d i s t i l l a t i o n apparatus to 190°C at a pressure of 0.2 mm. A colourless o i l (0.511 g) condensed i n the receiver, which was separated into three components by preparative glpc, (column A, 200°C). These components were, i n order of e l u t i o n ( r e l a t i v e y i e l d ) : o-methoxyacetophenone (64.5), mp 36-38, mixed mp 36-38°C. Z_-4-(2-methoxyphenyl)-pent-3-en-2-one (162) (8.5); i r (CHCI3) 1675 (unsaturated C=0) and 1600 cm"1 (C=C); uv (CH3OH) 295 (shoulder) and 272 nm. -118-E-4-(2-methoxyphenyl)-pent-3-en-2-one (162), (27); i r (CHC13) 1675 (unsaturated C=0) and 1600 cm - 1 (C=C); uv ( C H 3 O H ) 296 (shoulder) and 272 nm; nmr (CC1.J 67.30 - 6.70 (m, 4, a r y l protons), 6.10 (m, 1, C=C-H), 3.47 (d, J=0.9 Hz, 3, OCH 3), 2.33 (d, J=l Hz, 3, C=C-CH3) and 2.13 ppm (s, 3, C0-CH 3); mass spectrum m/e ( r e l intensity) 190(5), 175(10), 161(12), 160(100), 147 (4), 131 (40), 115(7), 105 (5), 91 (14), 77 (9), 63(5) , 51(7) , and 43 (76) ; analysis calcd for C l 2H 1 1 +0 2: C 75.76 H 7.42 found: C 75.61 H 7.61 Methyl 5-hydroxy-3-oxo-5-phenylpentanoate (150e) This compound was prepared by the same procedure as that employed i n the preparation of methyl 5-hydroxy-5-(2-methoxyphenyl)-3-oxohexanoate (150n). The reagents used i n the preparation were: sodium hydride, as a 57% mineral o i l dispersion, (0.466 g, 11.0 mmole), methyl acetoacetate (1.161 g, 10.0 mmole), n-butyllithium, as a 2.35M solution i n hexane, (4.5 ml, 10.6 mmole), and benzaldehyde (1.168 g, 11.0 mmole), which gave 2.553 g of crude 150e, as a yellow o i l . The crude product was p u r i f i e d by chromatography on a s i l i c a gel (200 g) column using a mixture of chloroform and ethyl acetate (9:1 v/v) as eluent. The major component from the chromatography was 150e (1.973 g, 89%). -119-i r (CHCI3) 3500 (O-H), 1740 (ester C=0) and 1705 cm - 1 (C=C); uv (CH3OH) 280 (shoulder), 264, 258, 252 and 247 nm; nmr {CClk) 67.22 (s, 5, a r y l protons), 5.05 (m, 1, HOCH), 3.65 (s, 3, OCH3), 3.33 (s, 2, COCH^C02Me), 3.30 (broad s, exchangeable D 20, 1, OH) and 2.79 ppm (m, 2, HOCCH2CO). mass spectrum a) high resolution calcd for C 1 2H l l t0i t 222.089 amu, found 222.086 m/e; b) low resolution m/e ( r e l intensity) 222 (20), 204 (74), 190 (21), 188 (18), 162 (30), 149 (58), 131 (77), 116(86), 107 (98), 106 (88), 105 (90), 91 (32), 85 (53), 84 (72), 77 (94), 58 (90), 51 (78), and 43 (100). Methyl 3-oxo-5-phenyl-5-trimethylsiloxypentanoate (151e) This compound was prepared by the same procedure as that employed i n the preparation of methyl 5-(2-methoxyphenyl)-3-oxo-trimethysiloxyhexanoate (151n). The reagents used were: methyl 5-hydroxy-3-oxo-5-phenylpentanoate (150e) (0.208 g, 0.93 mmole), chlorotrimethylsilane (0.108 g, 1.00 mmole) and hexamethyldisilazane (0.080 g, Q.50 mmole), which gave 0.153 g (52%) of 151e, bp 60-62° (0.2 mm). i r (CHCI3) 1740 (ester C=0), 1705 (C=0) and 1080 cm"1 (Si-OC); nmr (CC1 4, ext TMS) 7.23 (s, 5, a r y l protons), 5.20 -4.87 (m, 1, SiOCH) , 3.63 (s, 3, OCH 3), 3.27 (s, 2, COCH^CO^e) , - 1 2 0 -2.93 - 2.27 (m, 2, ArCCH 2CO) and 0.00 ppm ( s , 9, ( C H 3 ) 3 S i ) ; mass spectrum m/e ( r e l i n t e n s i t y ) 2 9 4 ( 1 ) , 2 7 9 ( 4 ) , 2 6 4 ( 3 ) , 249 ( 8 ) , 221 ( 1 6 ) , 204 ( 5 1 ) , 189 ( 1 2 ) , 179 ( 5 3 ) , 162 ( 3 4 ) , 149 ( 3 8 ) , 144 ( 5 2 ) , 131 ( 6 2 ) , 117 ( 4 5 ) , 116 ( 6 6 ) , 105 ( 7 6 ) , 91 ( 6 8 ) , 85 ( 5 4 ) , 77 ( 8 2 ) , 69 ( 6 2 ) , 59 (1 0 0 ) , and 43 (8 3 ) ; a n a l y s i s c a l c d f o r C ^ H ^ O ^ S i : C 61.19 H 7.53 foun d : C 61.40 H 7.32 M e t h y l 5-hydroxy-5-(2-methoxyphenyl)-3-oxopentanoate (150f) T h i s compound was p r e p a r e d by t h e same p r o c e d u r e as t h a t employed i n t h e p r e p a r a t i o n o f m e t h y l 5-hydroxy-5-(2-methoxyphenyl)-3-oxohexanoate (150n). The r e a g e n t s used were: sodium h y d r i d e , as a 57% m i n e r a l o i l d i s p e r s i o n , (0.465 g, 11.0 mmoles), m e t h y l a c e t o a c e t a t e (1.160 g, 10.0 mmoles), n - b u t y l l i t h i u m , as a 2.34M s o l u t i o n i n hexane, (4.5 ml , 10.6 mmole) and o-methoxybenzaldehyde (1.498 g, 11.0 mmole) w h i c h gave 2.830 g o f c r u d e 150f as a y e l l o w o i l . P u r i f i c a t i o n o f t h i s o i l was a c h i e v e d by t i c : c r u d e 150f (374 mg) was chromatographed on a 20 x 20 cm s i l i c a c o a t e d v p l a t e , a d s o r b a n t t h i c k n e s s 0.9 mm, u s i n g a m i x t u r e o f c h l o r o f o r m and e t h y l a c e t a t e (9:1 v/v) as e l u e n t . A f t e r e l u t i o n , t h e band l y i n g i n t h e r e g i o n 0.2 - 0.3 was removed and e x t r a c t e d w i t h e t h e r (20 m l ) . The s o l v e n t was removed by e v a p o r a t i o n under reduced p r e s s u r e t o g i v e 243 mg (73% e x t r a p o l a t e d ) o f 150f. -121-i r (CHC13) 3600 (O-H), 1740 (ester C=0) and 1705 cm"1 (C=0) ; nmr (CCI4) 67.50 - 6.67 (m, 4, a r y l protons), 5.30 (m, 1, HOCH), 3.83 (s, 3, a r y l OCH3) , 3.68 (s, 3, ester OCH 3), 3.50 (broad s, exchangeable D 2 0 , 1, OH), 3.36 (s, 2, COCH2CO^Me) and 2.77 ppm (m, 2, HOCCH2CO); uv(CH3OH) 276, 271 and 257 nm; mass spectrum a) high r e s o l u t i o n : calcd for C 1 3 H 1 6 0 5 , 252.099 amu, found 252.102 m/e; b) low resolution m/e (rel intensity) 252 (4), 234 (36), 203 (26), 179 (16), 175 (19) , 161 (43) , 151 (44), 137 (60), 133 (100), 127 (36), 121 (51), 116 (39), 105 (58), 91 (47), 85 (65), 77 (54), 59 (50) and 43 (70). Methyl 5-(2-methoxyphenyl)-3-oxo-5-trimethylsiloxypentanoate (151f) This compound was prepared by the same procedure as that employed i n the preparation of methyl 5-(2-methoxyphenyl)-3-oxo-5-trimethylsiloxyhexanoate (151n). The reagents used i n the preparation were: methyl 5-hydroxy-5-(2-methoxyphenyl)-3-oxopentanoate (150f) (149 mg, 0.59 mmole), chlorotrimethyl-silane (69 mg, 0.64 mmole) and hexamethyldisilazane (52 mg, 0.32 mmoles) , which gave 138 mg (71%) of 151f, bp 64-65° (0.5 mm). i r (CHC13) 1740 (ester C=0), 1705 (C=0) and 1070 cm"1. (Si-OC); -122-nmr (CCli+, ext TMS) 7.47 - 6,.60 (m, 4, a r y l protons), 5.43 (m, 1, ArCH), 3.80 (s, 3, a r y l OCH 3), 3.63 (s, 3, C0 2CH 3), 3.30 (s, 2, COCH2C02Me), 2.63 (m, 2, ArCCH2CO) and 0.00 ppm (s, 9, OSi(CH 3) 3) ; mass spectrum m/e ( r e l intensity) 324(7), 306(45), 293 (10), 266 (8), 251 (15), 241 (31),, 209 (97), 199 (24), 195 (17), 179 (25), 173 (95), 161 (33), 145(25), 135(53), 127 (24), 115(37), 105(53), 91(69), 85(20), 77 (68), 75 (92), 73 (100), 60 (22), 59 (66) ,-and 43 (88) ; analysis calcd for C 1 6H 2 ) +0 ; : )Si: C 59.23 H 7.46 found: C 59.46 H 7.48 Methyl 5-(2-furyl)-5-hydroxy-3-oxopentanoate (150h) This compound was prepared by the same procedure as that employed i n the preparation of methyl 5-hydroxy-5-methyl-3-oxo-hexanoate (150i). The reagents used i n the preparation were sodium hydride, as a 57% mineral o i l dispersion, (0.463 g, 11.0 mmoles), methyl acetoacetate (1.160 g, 10.0 mmole), n-butyllithium, as a 2.34M solution i n hexane, (4.5 ml, 10«6 mmole) and 2-furfuraldehyde (1.061 g, 11.0 mmole), which gave 1.445 g (68%) of 150h, bp 82-84° (0.1 mm). i r (CECI3) 3600 (O-H), 1740 (ester C=0) and 1710 cm - 1 (C=0); ; nmr {CClk) 67.32 (m, 1, H on C 5 of f u r y l r i n g ) , 6.23 -123-(m, 2, H on C 3 and Ci> of f u r y l r i n g ) , 5.05 (m, 1, HOCH), 3.82 (broad s, exchangeable D 20, 1, OH), 3.69 (s, 3, OCH 3), 3.42 (s, 2, COCH2C02Me) and 2.93 ppm (m, 2, HOCCH2CO); mass spectrum m/e ( r e l intensity) 212 (12), 194(11), 149 (11), 121(50), 116 (30), 101(13), 97 (75), 96 (71), 95 (76), 69(26), 65(21), 59(35) and 43(100); analysis calcd for C 1 0H 1 2O 5: C 56.60 H 5.70 found: C 56.66 H 5.35 Methyl 5-hydroxy-3-oxo-5-phenylhexanoate (150m) This compound was prepared by the same procedure as that employed i n the preparation of methyl 5-hydroxy-5-(2-methoxyphenyl)-3-oxohexanoate (150n). The reagents used were: sodium hydride, as a 57% mineral o i l dispersion, (0.461 g, 11.0 mmole), methyl acetoacetate (1.163 g, 10 mmole), n-butyllithium, as a 2.34M solution i n hexane, (4.5 ml,. 10.6 mmole) and acetophenone (1.318 g, 11.0 mmole) which gave 2.801 g of crude 150m as a yellow o i l . P u r i f i c a t i o n of t h i s o i l was achieved by t i c : 563 mg of crude 150m was chromatographed on a 20 x 20 cm s i l i c a coated plate, adsorbant thickness 0.9 mm, using a mixture of chloroform and ethyl acetate (9:1 v/v) as eluent. Aft e r e l u t i o n , the band l y i n g i n the region R f 0.25 - 0.40 was removed and extracted with ether (20 ml). The solvent was removed under reduced pressure to give 367 mg of 150m (extrapolated y i e l d 77%). -124-i r (CHCI3) 2550 (O-H), 1740 (ester C=0) and 1705 cm"1 (C=0); uv (CH3OH) 294 (shoulder), 278 and 273 nm; nmr (CC1H) 67.30 (m 5, a r y l protons), 3.85 (broad s, exchangeable D 20, 1, OH), 3.63 (s, 3, OCH 3), 3.25 (m, 2, C0CH 2C0 2Me), 2.67 (m, 2, HOCCH2CO) and 1.65 ppm (s, 3, CCH 3); mass spectrum a) high re s o l u t i o n calcd for C 1 3 H 1 6 0 H , 236.104 amu, found 236.105 m/e; b) low resolution m/e (rel intensity) 236 (2), 221 (5), 218 (5), 190(6), 170 (2), 159 (11), 145 (12), 127 (17), 121 (64), 120 (95), 116 (88), 106 (50), 105 (88), 101 (45), 85(95), 77 (100), 74 (95), 69 (64), 59 (97),and 43 (100). Methyl 3-oxo-5-phenyl-5-trimethylsiloxyhexanoate (151m) This compound was prepared by the same procedure as that employed for the preparation of methyl 5-(2-methoxyphenyl)-3-oxo-5-trimethylsiloxyhexanoate (151n). The reagents used were: methyl 5-hydroxy-3-oxo-5-phenylhexanoate (150m) (305 mg, 1.30 mmole), chlorotrimethylsilane (155 mg, 1.43 mmole) and hexamethyldisilazane (115 mg, 0.72 mmole), which gave 242 mg (61%) of 151m, bp 82-83° (0.3 mm). i r (CHCI3) 1740 (ester C=0), 1705 (C=0) and 1075 cm"1 (Si-OC) ; nmr (CC11+, ext TMS) 7.20 (m, 5, a r y l protons), 3.57 (s, 3, OCH3), 3.03 (m, 2, COCH2C02Me), 2.53 (m, 2, ArCCH 2CO), 1.66 (s, 3, CCH3) and 0.00 ppm (s, 9, OSi(CH 3) 3); -125-mass spectrum m/e ( r e l i n t e n s i t y ) 308 ( 1 ) , 295 ( 9 ) , 279 ( 7 ) , 264 ( 9 ) , 250 ( 4 ) , 233 ( 1 1 ) , 221 ( 5 ) , 211 ( 6 ) , 1 8 5 ( 1 0 0 ) , 179 (11) , 169 (46) , 156 ( 2 8 ) , 146 ( 1 2 ) , 126 ( 1 7 ) , 113 ( 4 8 ) , 101 ( 3 1 ) , 91(9) , 77 (26) and 73 (62) ; a n a l y s i s c a l c d f o r C x 6 H 2 i+Oi+Si : C 62.30 H 7.84 f o u n d : C 62.33 H 7.77 M e t h y l 5 - ( 2 , 3 - d i m e t h o x y p h e n y l ) - 5 - h y d r o x y - 3 - o x o p e n t a n o a t e (150g) T h i s compound was p r e p a r e d by t h e same p r o c e d u r e as t h a t employed f o r t h e p r e p a r a t i o n o f m e t h y l 5-hydroxy-5-(2-methoxyphenyl)-3-oxohexanoate (150n)• The r e a g e n t s used were: sodium h y d r i d e , as a 57% m i n e r a l o i l d i s p e r s i o n , (0.466 g, 11.0 mmole), m e t h y l a c e t o a c e t a t e (1.162 g, 10.0 mmole), n - b u t y l l i t h i u m , as a 2.34M s o l u t i o n i n hexane, (4.5 m l , 10.6 mmole) and 2,3-dimethoxybenzaldehyde (1.823 g, 11.0 mmole), w h i c h gave 3.044 g o f c r u d e 150g, as a p a l e brown o i l . P u r i f i c a t i o n o f 150g was a c h i e v e d by t i c : 3 06 mg o f c r u d e 150g was chromatographed on a 20 x 20 cm s i l i c a c o a t e d p l a t e , a d s o r b a n t t h i c k n e s s 0.9 mm, u s i n g a m i x t u r e o f c h l o r o f o r m and e t h y l a c e t a t e (9:1 v/v) as e l u e n t . A f t e r e l u t i o n , t h e band l y i n g i n t h e r e g i o n 0.30 - 0.40 was removed and e x t r a c t e d w i t h e t h e r (20 m l ) . The s o l v e n t was removed by e v a p o r a t i o n under reduced p r e s s u r e t o g i v e 194 mg o f 150g ( e x t r a p o l a t e d y i e l d , 6 8 % ) . i r (CHC13) 3550 (O-H), 1740 ( e s t e r C=0) and 1705 c m - 1 (C=0); -126-uv (CH3OH) 264 (shoulder), 256, 252 and 246 nm; nmr (CC1H) 66.93 (m, 3, a r y l protons)", 5.20 (m, 1, HOCH), 4.03 (broad s, exchangeable D 20, 1, OH), 3.80 (s, 6, a r y l OCH3), 3.67 (s, 3, ester 0CH3) , 3.37 (s, 2, COCH2C02Me) and 2.77 ppm (m, 2, HOCCH2CO); mass spectrum a) high resolution calcd for Ci^HisOe/ 282.110 amu, found 282.111 m/e; b) low resolution m/e ( r e l intensity) 282(19), 264 (7), 250(15), 233 (11), 22 (2), 217 (2), 209 (5), 205(4), 191 (9), 182 (3), 191 (9), 182 (3), 167 (100), 166 (46), 151(21), 139 (22), 137 (21), 116 (11), 107 (11), 91 (7), 85(10), 77 (21), 69 (9), 59 (15) and 43 (73). Methyl 5-(2,3-dimethoxyphenyl)-3-oxo-5-trimethylsiloxypentanoate (151g) This compound was prepared by the same procedure as that employed for the preparation of methyl 5-(2-methoxyphenyl)-3-oxo-5-trimethylsiloxyhexanoate (151n). The reagents used were: methyl 5-(2,3-dimethoxyphenyl)-5-hydroxy-3-oxopentanoate (173 g, 0.61 mmole), chlorotrimethyl-silane (74 mg, 0.68 mmole) and hexamethyldisolazane (55 mg, 0.34 mmole) which gave 114 mg (53%) of 151g, bp 89-91° (0.4 mm). i r (CHCI3) 1740 (ester C=0), 1705 (C=0) and 1075 cm"1 (Si-OC)% nmr (CC14 , ext TMS) 6 6.87 (m, 3, a r y l protons), 5.42 (m, 1, ArCH), 3.80 (s, 6, a r y l OCHj ) , 3.63 (s, 3, C0 2 CHj ) , 3.29 (s, 2, COCH2C02Me), 2.70 (m, 2, HOCCH^CO) and 0.00 ppm -127-( s , 9, O S i ( C H 3 ) 3) ; mass spectrum m/e ( r e l i n t e n s i t y ) 3 5 4 ( 1 6 ) , 3 2 3 ( 8 ) , 304 ( 4 ) , 241 ( 1 4 ) , 236 ( 1 0 0 ) , 223 ( 4 ) , 209 ( 8 ) , 193 ( 2 2 ) , 183 ( 4 7 ) , 165 ( 2 4 ) , 151 ( 1 3 ) , 149 ( 1 1 ) , 135 ( 1 3 ) , 1 2 1 ( 2 5 ) , 115 ( 2 1 ) , 1 0 5 ( 1 1 ) , 91 ( 1 1 ) , 89 ( 1 9 ) , 7 5 ( 4 4 ) , 73 ( 5 2 ) , 59 (17) and 4 3 ( 1 1 ) ; a n a l y s i s c a l c d f o r C 1 7 H 2 6 0 6 S i : C 57.60 H 7.40 fo u n d : C 57.80 H 7.29 M e t h y l 5 - h y d r o x y - 3 - o x o - 5 , 5 - d i p h e n y l p e n t a n o a t e (150p) T h i s compound was p r e p a r e d by t h e same p r o c e d u r e as t h a t employed f o r t h e p r e p a r a t i o n o f m e t h y l 5-hydroxy-5-(2-methoxyphenyl)-3-oxohexanoate (150n). The r e a g e n t s used were: sodium h y d r i d e , as a 57% m i n e r a l o i l d i s p e r s i o n , (0.466 g, 11.0 mmole), m e t h y l a c e t o a c e t a t e (1.160 g, 10.0 mmole), n - b u t y l l i t h i u m , as a 2.35M s o l u t i o n i n hexane, (4.5 m l , 10.6 mmole) and benzophenone (2.003 g, 11.0 mmole) w h i c h gave 3.124 g o f a s e m i - s o l i d . R e c r y s t a l l i s a t i o n from a hexane-e t h e r m i x t u r e gave a f i r s t c r o p o f 15Op (1.831 g ) . Subsequent c o n c e n t r a t i o n o f t h e mother l i q u o r s gave a second c r o p o f 150p (0.321 g) and f i n a l l y chromatography o f t h e r e s i d u a l s o l u t i o n on s i l i c a g e l (50 g) u s i n g c h l o r o f o r m as e l u e n t gave 0.622 g o f 150p, t o t o t a l 2.774 g (93%) o f p r o d u c t as c o l o u r l e s s n e e d l e s , mp 77-79°C. i r (CHCI3) 3550 (O-H), 1740 ( e s t e r C=0) and 1710 cm" 1 (C=0); -128-uv (CH3OH) 253 (785) , 259 (820) , 265 (685) and 269 nm (52) ; nmr (CC1H) 67.27 (m, 10, a r y l protons), 4.43 (broad s, exchangeable D 20, 1, OH), 3.67 (s, 3, OCH 3), 3.40 (s, 2, HOCCH2CO) and 3.27 ppm (s, 2, COCH2C02Me); mass spectrum m/e (rel intensity) 298(6), 207(22), 189 (14), 184 (66), 183 (98), 165 (11), 154 (18), 116 (10), 105 (100), 91(19), 77 (85), 69 (22), 59 (45), 51 (59) and 43 (60); analysis calcd for C i e H ^ O i + t C 72.47 H 6.08 found: C 72.47 H 6.05 Ethyl 5-hydroxy-3-oxo-5,5-diphenylpentanoate (152) This compound was prepared by the same procedure as that employed for the preparation of methyl 5-hydroxy-5-(2-methoxyphenyl)-3-oxohexanoate (150i). The reagents used were: sodium hydride, as a 57% mineral o i l dispersion, (0.465 g, 11.0 mmole), ethyl acetoacetate (1.303 g, 10.0 mmole) and benzophenone (2.001 g, 11.0 mmole), which gave 3.642 g of a yellow o i l . This o i l was dissolved i n cyclohexane and addition of a small quantity of methanol to the solution p r e c i p i t a t e d 152 (2.510 g, 81%) as colourless needles, mp 68-69°C ( l i t 2 3 mp 68.5-69.5°C). Methyl 4-(l-hydroxycyclohex-2-enyl)-3-oxobutanoate (164) This compound was prepared by the same procedure as that employed for the preparation of methyl 5-hydroxy-5--129-methyl-3-oxohexanoate (150i). The reagents used were: sodium hydride, as a 57% mineral o i l dispersion (0.467 g, 11.0 mmole), methyl acetoacetate (1.162 g, 10.0 mmole), n-butyllithium, as a 2.35M solution i n hexane, (4.5 ml,'." 10.6 mmole) and cyclohex-2-enone (0.962 g, 10.0 ,, o l e ) , which gave 2.210 g of pale yellow o i l . Careful d i s t i l l a t i o n of t h i s o i l i n base-washed apparatus gave 1.229 g (58%) of 164, bp. 83-85°C (0.1 mm) as a colourless o i l which r a p i d l y darkened on standing. i r (CC1.J 3600 (broad, O-H) , 1740 (ester C=0) , 1705 (C=0) and 1630 cm"1 (C=C-COH); nmr (CCl^) 65.67 (m, 2, v i n y l protons), 3.70 (s, 3, OCH 3), 3.40 (s, 2, COCH2C02Me), 2.83 (broad s, exchangeable D 20, 1, OH), 2.67 (s, 2, HOCCH2CO) and 2.10 - 1.46 ppm (m, 6, cyclohexyl protons on Cii_G) ; mass spectrum a) high resolution calcd for C i lH 1 6Oi +, 212.1048 amu, found 212.1063 m/e; b) low resolution m/e ( r e l intensity) 212 (8), 197 (12), 194 (13), 180 (15), 169 (23), 136 (27), 135(100), 134 (15), 121 (85), 108 (58), 97 (85), 96 (54), 91 (46), 84 (38), 79 (69), 77 (58), 68 (69), 55 (43) and 43 (77). Methyl 4-(3-hydroxycyclohex-l-enyl)-3-oxobutanoate (165) Sodium hydride, as a 57% mineral o i l dispersion, (0.465 g, 11.0 mmole) was weighed into an oven-dried 50 ml -130-f l a s k , and t e t r a h y d r o f u r a n (ca. 25 ml) was d i s t i l l e d , from l i t h i u m a l u m i n i u m h y d r i d e , d i r e c t l y i n t o t h i s f l a s k . The f l a s k was equ i p p e d w i t h a magnetic s t i r r e r , s t o p p e r e d (septum c a p ) , c o o l e d i n i c e t o 0°G and f l u s h e d w i t h n i t r o g e n . M e t h y l a c e t o a c e t a t e (1.160 g, 10.0 mmole) was added d r o p w i s e t o t h e c o o l e d s l u r r y and t h e r e a c t i o n a l l o w e d t o s t i r f o r t e n minutes a f t e r t h e a d d i t i o n was c o m p l e t e . A s o l u t i o n o f n - b u t y l l i t h i u m (4.5 m l , 2.35M i n hexane, 10.6 mmole) was added d r o p w i s e t o t h e s o l u t i o n and t h e m i x t u r e a l l o w e d t o s t i r f o r an a d d i t i o n a l t e n m i n u t e s , t o a l l o w c omplete f o r m a t i o n of t h e d i a n i o n . Cyclohex-2-enone (0.961 g, 10.0 mmole) was added i n one p o r t i o n t o t h e r e a c t i o n w h i c h was a l l o w e d t o s t i r f o r t e n mi n u t e s b e f o r e b e i n g quenched, w h i c h was a c h i e v e d by d r o p w i s e a d d i t i o n o f t h e r e a c t i o n , v i a a s t a i n l e s s s t e e l c a n n u l a , t o a v i g o r o u s l y s t i r r e d m i x t u r e o f e t h e r (ca. 50 ml) and h y d r o c h l o r i c a c i d (12 ml 2M s o l u t i o n ) . The aqueous and o r g a n i c phases were s e p a r a t e d . The aqueous phase was f u r t h e r e x t r a c t e d w i t h e t h e r (2 x 25 ml) and t h e e t h e r e a l phases combined, washed w i t h s a t u r a t e d sodium c h l o r i d e s o l u t i o n , d r i e d o v e r anhydrous sodium s u l p h a t e and f i l t e r e d . The s o l v e n t s were removed by e v a p o r a t i o n under reduced p r e s s u r e and t h e r e s u l t i n g o i l chromatographed on s i l i c a g e l u s i n g a m i x t u r e o f hexane,.ether and a c e t i c a c i d (50:100:1) as e l u e n t . The two major f r a c t i o n s were i d e n t i f i e d a s : me t h y l 4 - ( l - h y d r o x y c y c l o h e x - 2 - e n y l ) - 3 - o x o b u t a n o a t e (164) (0.703 g, 33%) by comparison o f i r and nmr s p e c t r a w i t h t h o s e -131-of 164 prepared previously, and methyl 4-(3-hydroxycyclohex-l-enyl)-3-oxobutanoate (165) (0.594 g, 28%), bp 100-101°C (0.1 mm). i r (CCln) 3650 (sharp, 0-H), 3500 (broad, O-H), 1740 (ester C=0), 1720 (C=0) and 1630 cm"1 (C=C-C0H); nmr (CDC13) 66.67 (m, 1, C=CH), 4.20 (m, 1, HOCH), 3.73 (s, 3, OCH3) , 3.48 (s, 2, COCH2COzMe), 3.20 (broad s, 2, C=C-CH2-CO), 2.30 (broad s, exchangeable D 20, 1, OH) and 2.00 - 1.34 ppm (m, 6, cyclohexyl protons on C\_ 6); mass spectrum a) high resolution calcd for CjiHieOit, 212.1048 amu, found 212.1088 m/e; b) low resolution m/e (rel intensity) 212 (1), 194 (22), 162(11), 161 (9), 136 (91), 121(100), 116 (37), 108 (85), 93 (57), 91 (52), 79 (39), 77 (33), 65(32), 59(15), 55 (26) and 43 (59). Attempted conjugate addition of dianion 132 to cyclohex-2-enone Sodium hydride, as a 57% mineral o i l dispersion, (0.465 g, 11.0 mmole) was weighed into an oven-dried 50 ml fl a s k , and tetrahydrofuran (ca. 25 ml) was d i s t i l l e d , from lithium aluminium hydride, d i r e c t l y into t h i s f l a s k . The fla s k was equipped with a magnetic s t i r r e r , stoppered (septum cap), cooled i n i c e to 0°C and flushed with nitrogen. Methyl acetoacetate (1.160 g, 10.0 mmole) was added dropwise to the cooled s l u r r y and the reaction allowed to s t i r for -132-ten minutes aft e r the addition was complete. A solution of n-butyllithium (4.5 ml 2.35M i n hexane, 10.6 mmole) was added dropwise to the solution and the mixture allowed to s t i r for an addit i o n a l ten minutes, to allow complete formation of the dianion. Cuprous iodide (4.208 g, 22.0 mmole), dried at 110° i n vacuo (0.1mm) for twenty hours p r i o r to use, was weighed under dry conditions into a 100 ml f l a s k and tetrahydrofuran d i s t i l l e d d i r e c t l y into t h i s flask from lithium aluminium hydride. The f l a s k was equipped with a magnetic s t i r r e r , stoppered (septum cap) and flushed with nitrogen. Both the solution of dianion and the cuprous iodide suspension were cooled i n a dry ice/acetone s l u r r y to ^ -78°C. The dianion solution was transferred, v i a a s t a i n l e s s s t e e l cannula, i n a dropwise manner to the f l a s k containing the cuprous iodide. The r e s u l t i n g dark brown mixture was s t i r r e d for an hour at the end of which time most of the s o l i d had dissolved. Cyclohex-2-enone (0.963 g, 10.0 mmole) dissolved i n tetrahydrofuran (ca. 5 ml) was added to the reaction which was maintained at -78°C for an addit i o n a l hour before being allowed to warm to 0°C. The reaction was quenched by dropwise addition of i t to a vigorously s t i r r e d mixture of ether (50 ml) and hydrochloric acid (12 ml 2M solution). The aqueous phase was separated and further extracted with ether (2 x 35 ml). The ethereal extracts were combined, washed with saturated sodium chloride solution (6 x 25 ml), dried over anhydrous sodium sulphate and f i l t e r e d . The solvents were removed by evaporation under reduced pressure and the -133-r e s u l t i n g o i l chromatographed on s i l i c a g e l u s i n g a m i x t u r e o f hexane, e t h e r and a c e t i c a c i d as e l u e n t . The major f r a c t i o n s were i d e n t i f i e d , by comparison o f i r and nmr s p e c t r a w i t h a u t h e n t i c o r p r e v i o u s l y p r e p a r e d m a t e r i a l s , a s : m e t h y l a c e t o a c e t a t e (0.708 g, 6 1 % ) , c y c l o h e x - 2 - e n o n e (0.564 g, 5 9 % ) , m e t h y l 4 - ( l - h y d r o x y c l o h e x - 2 - e n y l ) - 3 - o x o b u t a n o a t e (164) (0.360 g, 1 7 % ) , and m e t h y l 4 - ( 3 - h y d r o x y c y c l o h e x - l -e n y l ) -3-oxobutanoate (165) (0.276 g, 1 3 % ) . M e t h y l 5-hydroxy-5-methyl-3-oxohept-6-enoate (163) T h i s compound was p r e p a r e d by t h e same p r o c e d u r e as t h a t employed i n t h e p r e p a r a t i o n o f m e t h y l 5-hydroxy-5-methyl-3-oxohexanoate ( 1 5 0 i ) . The r e a g e n t s used i n t h e p r e p a r a t i o n were: sodium h y d r i d e , as a 57% m i n e r a l o i l d i s p e r s i o n , (0.466 g, 11.0 mmole), m e t h y l a c e t o a c e t a t e (1.163 g, 10.00 mmole), n - b u t y l l i t h i u m , as a 2.35M s o l u t i o n i n hexane, (4.5 m l , 10.6 mmole), and m e t h y l v i n y l k e t o n e (0.661 g, 11.0 mmole), w h i c h gave 1.450 g (78%) o f 163 bp 101-103°C (0.3 mm). i r (CHC1 3) 3550 (O-H), 1740 ( e s t e r C=G), 1705 (C=0) and 1630 c m - 1 (C=C-COH); nmr (CCl^) 65.87 (m, 1, C=CH), 5.10 (m, 2, C=CH 2), 3.72 ( s , 3, OCH 3), 3.36 ( s , 2, C0CH 2C0 2Me), 3.20 (broad s, exchangeable D 20, 1, OH), 2.20 (m, 2, HOCCH2CO) and 1.27 ppm ( s , 3, CCH 3) ; -134-mass spectrum a) h i g h r e s o l u t i o n , c a l c d f o r CgHiHOit, 186.0891 amu, found 186.0921 m/e b) low r e s o l u t i o n m/e ( r e l i n t e n s i t y ) 186 ( 1 ) , 171 ( 1 ) , 168 ( 3 ) , 139 ( 4 ) , 127 ( 6 ) , 116 ( 1 5 ) , 101 ( 1 0 ) , 97 ( 9 ) , 9 5 ( 8 ) , 8 5 ( 2 0 ) , 84 ( 1 4 ) , 74 ( 1 2 ) , 71 ( 3 1 ) , 6 9 ( 1 6 ) , 59 ( 2 6 ) , 55(60) and 43(100). Base Dependency Study a) G e n e r a t i o n o f D i a n i o n 132 by means o f L i t h i u m D i i s o p r o p y l -amide . D i i s p r o p y l a m i n e , w h i c h had been d r i e d by d i s t i l l a t i o n and s t o r e d o v e r p o t a s s i u m h y d r o x i d e p e l l e t s p r i o r t o use (1.129 g, 11.3 mmole) was weighed i n t o a 50 ml oven d r i e d f l a s k and t e t r a h y d r o f u r a n ( ca. 25 ml) d i s t i l l e d d i r e c t l y i n t o t h i s f l a s k from l i t h i u m a l u m i n i u m h y d r i d e . The f l a s k was equipped w i t h a mag n e t i c s t i r r e r , s t o p p e r e d (septum c a p ) , c o o l e d i n i c e and f l u s h e d w i t h n i t r o g e n , n - b u t y l l i t h i u m , as a 2.35M s o l u t i o n i n hexane, (5 m l ) , 11.75 mmole) was added d r o p w i s e t o t h e s o l u t i o n and t h e r e a c t i o n a l l o w e d t o s t i r f o r t e n m i n u tes a f t e r t h e a d d i t i o n was c o m p l e t e , t o ensure complete f o r m a t i o n o f t h e amide. M e t h y l a c e t o a c e t a t e (0.638 g, 5.5 mmole) was added d r o p w i s e t o s o l u t i o n and a f t e r a f u r t h e r t e n m i n u t e s , benzophenone (1.003 g, 5.5 mmole) d i s s o l v e d i n t e t r a h y d r o f u r a n (5 ml) was added. The r e a c t i o n was quenched a f t e r t e n mi n u t e s by a d d i t i o n o f c o n c e n t r a t e d h y d r o c h l o r i c a c i d (2 ml) and worked up by t h e a d d i t i o n o f -135-ether (50 ml) and water (15 ml). The aqueous phase was separated and further extracted with ether (2 x 35 ml). The ethereal extracts were combined, washed with saturated sodium chloride solution (4 x 35 ml), dried over anhydrous sodium sulphate and f i l t e r e d . The solvents were removed by evaporation under reduced pressure to give a semi-solid which was r e c r y s t a l l i s e d from a mixture of hexane and ether to give 0.827 g of methyl 5-hydroxy-3-oxo-5,5-diphenylpentanoate (150p). Chromatography of the mother liquors on s i l i c a gel using chloroform as eluent gave an additional 0.184 g of 150p, to t o t a l 1.011 g (62%) as colourless needles, mp 77-79°C. b) Attempted Generation of Dianion 132 by means of Lithium bis-(trimethylsilyl)amide Lithium b i s - ( t r i m e t h y l s i l y l ) a m i d e was prepared by 92 the method of Shaw, from hexamethyldisilazane and n-butyllithium, and dissolved i n tetrahydrofuran. This solution was standardised by t i t r a t i o n against hydrochloric acid to determine i t s t o t a l base equivalence. An aliquot of th i s solution, which had been found to be 1.52M (5 ml, 7.60 mmole) was dil u t e d to 25 ml with tetrahydrofuran and transferred to a 50 ml oven dried f l a s k . The fl a s k was equipped with a magnetic s t i r r e r , stoppered (septum cap), cooled i n i c e and flushed with nitrogen. Methyl acetoacetate (0.420 g, 3.62 mmole) was added dropwise to the solution of base and the -136-reaction allowed to s t i r for one hour a f t e r the addition was complete. Benzophenone (0.655 g, 3.65 mmoles) dissolved i n tetrahydrofuran (3 ml) was added to the reaction which was quenched a f t e r a further f i f t e e n minutes by addition of concentrated hydrochloric acid (0.75 ml). The reaction was worked up by the addition of ether (25 ml) and water (5 ml). The aqueous layer was separated and further extracted with ether (2 x 25 ml). The ethereal extracts were combined, washed with saturated sodium chloride solution (4 x 25 ml), dried over anhydrous sodium sulphate and f i l t e r e d . The solvents were removed by evaporation under reduced pressure to a pale yellow o i l . Glpc analysis (col B, 110°C) indicated that t h i s o i l was mainly methyl acetoacetate contaminated with hexamethyldisolazane and benzophenone, and d i s t i l l a t i o n at reduced pressure gave e s s e n t i a l l y pure methyl acetoacetate (0.352 g, 84%). No product could be detected by glpc or t i c either i n the crude o i l or the residue from the d i s t i l l a t i o n , that was not s t a r t i n g materials or hexamethyldisilazane. Temperature Dependency Study The dianion of methyl acetoacetate was generated as outlined below and then treated with propanal at low and room temperature. -137-Generation of Dianion 132 Sodium hydride, as a 57% mineral o i l dispersion, (0.465 g, 11.0 mmole) was weighed into an oven-dried 50 ml fl a s k , and tetrahydrofuran (ca. 25 ml) was d i s t i l l e d from li t h i u m aluminium hydride d i r e c t l y into t h i s f l a s k . The fla s k was equipped with a magnetic s t i r r e r , stoppered (septum cap), cooled i n i c e to 0°C and flushed with nitrogen Methyl acetoacetate (1.160g, 10.0 mmole) was added dropwise to the cooled s l u r r y and the reaction allowed to s t i r f or ten minutes afte r the addition was complete. A solution of n-butyllithium (4.5 ml 2.35M i n hexane, 10.6 mmole) was added dropwise to the solution and the mixture allowed to s t i r for an additional ten minutes, to allow complete formation of the dianion. Reaction of Dianion 132 with Propanal at -78°C The solution of dianion 132 was cooled to -78 WC in a dry ice/acetone s l u r r y , and propanal (0.640 g, 11.0 mmo added. The reaction was s t i r r e d at -78°C for one hour and then allowed to warm to 0°C before being quenched with concentrated hydrochloric acid (2 ml). The reaction was worked up by the addition of ether (25 ml) and water (5 ml). The aqueous phase was separated and further extracted with ether (2 x 35 ml). The ethereal extracts were combined, washed with saturated sodium chloride solution (6 x 25 ml), dried over sodium sulphate and f i l t e r e d . The solvents were -138-removed by evaporation at reduced pressure and the r e s u l t i n g o i l d i s t i l l e d under high vacuum to give methyl acetoacetate (0.915 g, 79% recovery), i d e n t i f i e d by glpc analysis, (col B, 110°C) and comparison of i t s i r spectrum with that of authentic material, and methyl 5-hydroxy-3-oxoheptanoate (150b) (0.191 g, 11%), i d e n t i f i e d by comparison of i t s i r and nmr spectra with those of previously prepared 150b. Reaction of Dianion 13 2 with Propanal at 25°C The solution of dianion 132 was allowed to warm to room temperature before propanal (0.641 g, 11.0 mmole) was added. The reaction was s t i r r e d at room temperature for one half hour before being quenched with concentrated hydrochloric acid (2 ml). The reaction was worked up i n an i d e n t i c a l manner to the previous low temperature reaction to give 0.993 g (57%) of 150b, bp 48-49°C (0.2 mm), which showed i d e n t i c a l i r and nmr spectra to that prepared previously. Claisen Condensations of the Dianion of Beta-ketoesters Methyl 3,5-dioxohexanoate (176a) Sodium hydride, as a 57% mineral o i l dispersion, (0.467 g, 11.0 mmole) was weighed into a 50 ml oven dried flask and tetrahydrofuran (ca. 25 ml) was d i s t i l l e d d i r e c t l y into t h i s f l a s k from lithium aluminium hydride. The fl a s k was equipped with a magnetic s t i r r e r , stoppered (septum cap), -139-cooled i n i c e and flushed with nitrogen. Methyl acetoacetate (1.160 g, 10.0 mmole) was added dropwise to the cooled sl u r r y and the reaction allowed to s t i r f or ten minutes af t e r the addition was complete. n-Butyllithium, as a 2.1M solution i n hexane, (5 ml, 10.5 mmole) was added dropwise to the reaction and a f t e r ten minutes the f i r s t portion of methyl acetate, (0.372 g, 5.0 mmole) was added. After a further f i f t e e n minutes, additional n-butyllithium (5 ml, 10.5 mmole) was added very slowly. A further period of f i f t e e n minutes was allowed to elapse before the second portion of methyl acetate (0.371 g, 5.0 mmole) was added and the reaction s t i r r e d for a f i n a l f i f t e e n minutes before being quenched with concentrated hydrochloric acid (3 ml). The reaction was worked up by the addition of ether (35 ml) and water (10 ml). The aqueous phase was separated and further extracted with ether (2 x 35 ml). The ethereal extracts were combined, washed with saturated sodium hydrogen carbonate solution (2 x 10 ml) and with saturated sodium chloride solution (4 x 15 ml)„ dried over anhydrous sodium sulphate and f i l t e r e d . The solvents were removed by evaporation under reduced pressure and the r e s u l t i n g yellow o i l d i s t i l l e d under high vacuum to give 1.120 g (71%) of 176a, bp 44-46°C (0.3 mm). i r (CHC13) 3450 (C=C-0-H), 1740 (ester C=0) and 1600 cm"l (broad, 0=C-C=C-OH),° -140-nmr (CDCI3) 614.2 (broad s, exchangeable D2O, 1, C=C0H), 5.62 (s, 0.67, C=CH), 3.79 (s, 3, OCH 3), 3.57 (s, 0.64, COCH2CO), 3.35 (s, 2, COCH 2C0 2Me), 2.27 (s, 0.95, CH3CO) and 2.10 ppm (s, 2.13, CH3C=C), 68% enol; mass spectrum m/e ( r e l intensity) 158(6), 127(6), 126(8), 116(8), 107(8), 101(6), 98(9), 91(9), 85(43), 77 (6), 69 (21), 59 (10) and 43 (100); analysis calcd for C7E1QOk: C 53.16 H 6.37 found: C 53.14 H 6.26 Methyl 3,5-dioxooctanoate (170c) This compound was prepared by the same procedure as that employed i n the preparation of methyl 3,5-dioxohexanoate (170a). The reagents used i n the preparation were: sodium hydride, as a 57% mineral o i l dispersion, (0.465 g, 11.0 mmole), methyl acetoacetate (1.161 g, 10.0 mmole), two portions of n-butyllithium, as a 2.35M s o l u t i o n i n hexane, (4.6 ml, 10.6 mmole) which gave 1.250 g (67%) of 170c, bp 83-85°C (0.1 mm). i r (CCI4) 3500 (C=C-0-H), 1740 (ester C=0) and 1595 cm"1 (H0-C=C-C=0); nmr (CCl^) 614.3 (broad s, 0.97, C=C-OH), 5.52 (s, 0.98, C=CH), 3.66 (s, 3, OCH3), 3.20 (s, 1.96, COCH2C02Me), 2.26 (t, J=7Hz, CH2CH2C=C), 1.66 (m, 2.0, CH 3CH 2CH 2) and 0.96 ppm (t, J=7Hz, 3.0, CH 3CH 2), 97% enol; -141-mass spectrum m/e ( r e l intensity) 186(41), 172(22), 158 (68), 157 (57), 143 (81) , 126 (73) , 115 (62) , 113 (92) , 101(100), 97 (28), 85 (73), 84 (72), 71 (90), 69 (51), 59 (81) and 43(17); analysis calcd for C g H ^ O ^ : C 58.05 H 7.58 found: C 58.35 H 7.47 Condensation of ethyl butanoate with dianion 132 This reaction was performed i n a s i m i l a r manner to that i n which methyl 3,5-dioxohexanoate was prepared. The reagents used were: sodium hydride, as a 57% mineral o i l dispersion, (0.466 g, 11.0 mmole), methyl acetoacetate (1.161 g, 10o0 mmole), two portions of n-butyllithium, as a 2.35M solution i n hexane, (4.5 ml, 10.6 mmole) and two portions of ethyl butanoate (0.582 g, 5.0 mmole), which gave 1.441 g of a pale yellow o i l . Glpc analysis (col C, 140°C) of t h i s o i l showed i t to contain two components. D i s t i l l a t i o n through a short Vigreux column gave p a r t i a l separation of these components and repeated d i s t i l l a t i o n (three more times), although accompanied by considerable r e s i n i f i c a t i o n of the o i l , gave the pure components i d e n t i f i e d as: methyl 3,5-dioxooctanoate (176c) (0.619 g, 33%) by comparison of i r and nmr spectra with those of previously prepared 176c, and, ethyl 3,5-dioxooctanoate (177), (0.223 g, 11%) bp 94-96°C (0.1 mm). -142-i r (CClu) 3500 (C=C-OH), 1740 (ester C=0) and 1600 cm - 1 (HO-C=C-C=0); nmr (CC14) 614.6 (broad s, exchangeable D 20, 1, OH), 5.57 (S, 1, C=CH), 4.13 (q, H=7Hz, 2, OCH 2CH 3), 3.08 (s, 2, COCH2C02Me), 2.27 (t, J=7Hz, 2, CH 2CH 2CO), 1.65 (m, 2, CH 3CH 2CH 2), 1.27 (t, J=7Hz, 2, OCH2CH3) and 0.95 ppm (t, J=7Hz, 3, CH 2CH 2CH 3); mass spectrum m/e ( r e l intensity) 200(20), 156(47), 143 (78), 126 (70), 115 (64), 113 (80), 101 (100), 97 (30), 85 (74), 84 (70), 71 (85), 69 (15), 59 (60) and 43 (28); analysis calcd for C^oH^O^: C 59.98 H 8.05 found: C 59.98 H 8.08 Methyl 3,5-dioxopentanoate (176b) This compound was prepared by the same procedure as that employed i n the preparation of methyl 3,5-dioxohexanoate (176a). The reagents used i n the preparation were: sodium hydride, as a 57% mineral o i l dispersion, (0.466 g, 11,0 mmole), methyl acetoacetate (1.160 g, 10.0 mmole), two portions of n-butyllithium, as a 2.35M solution i n hexane, (4.5 ml, 10.6 mmole) and two portions of methyl formate (0.300 g, 5.0 mmole), which gave 0„993 g (69%) of 176b, bp 55-56°C (0.1 mm). i r (CCl^) 3500 (C=C-0-H), 1740 (ester C=0), 1640 (chelated C=0) and 1590 cm_l' (C=C) ; -143-nmr (CCI14) 613.5 (broad s, exchangeable D 20, 1, OH), 7.72 (d, J=5Hz, 1, CH=CH-OH), 5.63 (d, J=5Hz, 1, C=CH), 3.72 (s, 3, OCH3), and 3.32 ppm (s, 2, COCH2C02Me); mass spectrum m/e a) high resolution calcd for C H O : 144.0422 amu, found 144.0421 m/e; b) m/e ( r e l intensity) 144(5), 131(3), 127 (2), 126 (11), 113 (15), 112 (17), 101 (100), 97 (30), 85(67), 71 (63) , 59 (43) and 43 (28) . Condensation of methyl benzoate with dianion 132 Sodium hydride, as a 57% mineral o i l dispersion, (0.468 g, 11„0 mmole) was weighed into a 50 ml oven dried flask and tetrahydrofuran (ca. 25 ml) was d i s t i l l e d d i r e c t l y into t h i s flask from lithium aluminium hydride. The fl a s k was equipped with a magnetic s t i r r e r , stoppered (septum cap), cooled i n ice and flushed with nitrogen. Methyl acetoacetate (1.164 g, 10o0 mmole) was added dropwise to the cooled s l u r r y , and a f t e r the addition was complete the reaction was allowed to s t i r for ten minutes. n-Butyllithium, as a 2.1M solution i n hexane, (5 ml, 10.5 mmole) was added dropwise to the reaction and afte r ten minutes the f i r s t portion of methyl benzoate (0.680 g, 5.0 mmole) was added. After a further f i f t e e n minutes additional n-butyllithium (5 ml, 10.5 mmole) was added very slowly. A further period of f i f t e e n minutes was allowed to elapse before the second portion of methyl benzoate (0.680 g, 5.0 mmole) was added and the reaction was -144-s t i r r e d for a f i n a l f i f t e e n minutes before being quenched with concentrated hydrochloric acid (3 ml). The reaction was worked up by the addition of ether (35 ml) and water (10 ml). The aqueous phase was separated and further extracted with ether (2 x 35 ml). The ethereal extracts were combined, washed with saturated sodium hydrogen carbonate solution (4 x 15 ml) and with saturated sodium chloride solution (2 x 15 ml), dried over anhydrous sodium sulphate and f i l t e r e d . The solvents were removed by evaporation under reduced pressure and the r e s u l t i n g red o i l d i s t i l l e d under high vacuum to give 0.817 g (37%) of methyl 3,5-dioxo-5-phenylpentanoate (176d), bp 127-129°C (0.1 mm), characterised as outlined below. The basic aqueous extract (saturated sodium hydrogen carbonate washings) were a c i d i f i e d to pH 2 by addition of IM hydrochloric acid and the r e s u l t i n g solution extracted with ether (3 x 35 ml) and these ethereal extracts combined, washed with saturated sodium chloride solution (3 x 15 ml), dried over sodium sulphate and f i l t e r e d . The solvents were removed by evaporation under reduced pressure and the r e s u l t i n g s o l i d r e c r y s t a l l i s e d from a mixture of hexane and ether to give 0.684 g (30%) of 3,5-dioxo-5-23 phenylpentanoic acid (178d) mp 93-97°C, ( l i t e r a t u r e mp 94-96°C)o Methyl 3,5-dioxo-5-phenypentanoate was characterised by: -145-i r (CCliJ 3450 (C=C-0-H), 1740 (ester C=0) and 1600 cm"1 (HOC=C-C=0) ; uv (CH3OH) 322 nm (1.3 x 10 3); nmr (CC14) 614.3 (broad s, exchangeable D 20, 1, OH), 7.87 (m, 2, protons on C 2 and Ce of benzene r i n g ) , 7.37 (m, 3, protons on C 3, C H and C 5 of benzene r i n g ) , 6.26 (s, 1, C=CH), 3.70 (s, 3, OCH3) and 3.38 ppm (s, 2, COCH2C02Me); mass spectrum m/e ( r e l intensity) 220(21), 205(11), 203 (34), 189 (26), 188 (65), 174 (16), 173 (11), 163 (57), 161(58), 147 (74), 105 (100), 85 (15), 77 (48), 69 (51), 51 (37) and 43 (28); analysis calcd for C 1 2 H 1 2 0 4 : C 65.45 H 5.49 found: C 65.42 H 5.65 Condensation of methyl 4-methoxybenzoate with dianion 132 This reaction was performed i n a s i m i l a r manner to the condensation of methyl benzoate with dianion 132. The reagents used were: sodium hydride, as a 57% mineral o i l dispersion, (0.467 g, 11.0 mmole), methyl acetoacetate (1.161 g, 10.0 mmole), two portions of n-butyllithium, as a 2.35M solution i n hexane, (4.5 ml, 10.6 mmole) and two portions of methyl 4-methoxybenzoate (0.831 g, 5.0 mmole) which gave 0.741 g (29%) of 5-(4-methoxyphenyl)-3,5-dioxopentanoic acid (178e), as colourless needles (from hexane/ether) mp 103-105°C, and 1.051 g (42%) of methyl 5-(4-methoxyphenyl)-3,5-dioxopentanoate (176e), bp 142-143°C - 1 4 6 -( 0 . 1 mm). These compounds were characterised as follows: a) 5-(4-methoxyphenyl)-3,5-dioxopentanoic acid i r ( C H C 1 3 ) 3 7 0 0 (sharp, non-hydrogen bonded C 0 2 H ) , 3 5 0 0 (hydrogen bonded C 0 2 H and C = C - O H ) , 1 7 2 0 (carboxylic acid C = 0 ) and 1 6 0 0 cm-1 ( 0 = C - C = C - O H ) ; uv ( C H 3 0 H ) 3 2 6 ( 7 . 1 x 1 0 ) and 2 8 7 nm (shoulder, 4.4 x 1 0 3 ) ; nmr (CD3COCD3) 6 1 4 . 6 (broad s, exchangeable D 2 0 , 1 , enol O H ) , 1 1 . 2 (broad s, exchangeable D 2 0 , 1 , C 0 2 H ) , 7 . 8 7 (m, 2 , protons on C 3 and of benzene r i n g ) , 6 . 9 3 (m, 2 , protons on C 2 and C 5 of benzene r i n g ) , 3 . 9 0 (s, 3 , O C H 3 ) and 3 . 3 7 ppm (s, 2 , C O C H 2 C 0 2 H ) ; mass spectrum m/e ( r e l intensity) 2 3 7 ( 5 ) , 2 3 6 ( 4 3 ) , 2 1 9 ( 5 ) , 2 1 8 ( 4 2 ) , 1 9 3 ( 4 3 ) , 1 9 2 ( 9 6 ) , 1 9 1 ( 6 7 ) , 1 7 8 ( 5 0 ) , 1 7 7 ( 8 4 ) , 1 6 1 ( 6 8 ) , 1 4 9 ( 2 0 ) , 1 3 6 ( 5 7 ) , 1 3 5 ( 1 0 0 ) , 1 2 1 ( 2 1 ) , 1 0 9 ( 7 5 ) , 1 0 8 ( 5 7 ) , 1 0 5 ( 1 5 ) , 9 2 ( 3 2 ) , 8 5 ( 3 0 ) , 7 7 ( 3 7 ) , 6 9 ( 4 5 ) , 5 1 ( 3 5 ) , 4 4 ( 4 0 ) and 4 3 ( 3 5 ) ; analysis calcd for C 1 2 H 1 2 0 5 : C 6 1 . 0 2 H 5 . 1 2 found: C 6 1 . 0 8 H 5 . 2 6 b) methyl 5-(4-methoxyphenyl)-3,5-dioxopentanoate: i r (CClk) 3 5 0 0 (enol O H ) , 1 7 4 0 (ester C = 0 ) and 1 6 0 0 cm"1 ( 0 = C - C = C - 0 H ) ; uv (CH3OH) 3 2 5 ( 5 . 4 x 1 0 ) and 2 8 5 nm (shoulder, 2.0 x 1 0 3 ) ; nmr (CCIL,) 6 1 4 . 3 (broad s, exchangeable D 2 0 , 1 , O H ) , 7 . 8 5 (m, 2, protons on C 3 and C 5 of benzene r i n g ) , 6 . 9 0 -147-(m, 2, protons on C 2 and C6 of benzene r i n g ) , 6.20 (s, 1, C=CH), 3.90 (s, 3, a r y l OCH3) , 3.77 (s, 3, ester OCH3) and 3.47 ppm (s, 2, C0CH2C02Me); mass spectrum m/e (rel intensity) 250(21), 217(57), 190 (44), 177 (65), 135 (100), 109 (23), 108 (13), 107 (15), 105(16), 104 (32), 91 (29), 77 (29), 69(65), 59(23),and 43 (55); analysis calcd for C13Hll405: C 62.39 H 5.64 found : C 62.4 3 H 5.72 Base Dependency Study a) Lithium diisopropylamide. (i) Attempted acylation with methyl acetate. Diisopropylamine (1.536 g, 15.0 mmole) was weighed into an oven-dried f l a s k , and tetrahydrofuran (ca. 25 ml) was d i s t i l l e d d i r e c t l y into t h i s f l a s k from lithium aluminium hydride. The fask was equipped with a magnetic s t i r r e r , stoppered (septum cap), cooled i n i c e and flushed with nitrogen. n-Butyllithium, as a 2.1M solution i n hexane, (7.5 ml, 15.8 mmole) was added dropwise to the cooled solution and the reaction allowed to stand for ten minutes a f t e r the addition was complete. Methyl acetoacetate (0.580 g, 5.0 mmole) was added to the reaction over a period of about ten minutes and a further period of ten minutes allowed to elapse before methyl acetate, (0.370 g, 5.0 mmole) was added. After ten minutes the reaction was quenched with concentrated hydrochloric acid (ca. 4 ml) and the reaction worked up by the -148-addition of ether (35 ml) and water (10 ml). The aqueous phase was separated and further extracted with ether (2 x 35 ml). The ethereal extracts were combined, washed with water (3 x 20 ml) and with saturated sodium chloride solution (2 x 20 ml), dried over anhydrous sodium sulphate and f i l t e r e d . The solvents were removed by evaporation at reduced pressure to give 0.601 g of pale yellow o i l . Glpc analysis of t h i s o i l (col C, 120°C) showed i t to be methyl acetoacetate contaminated with minor amounts of diisopropylamine and methyl acetate. Both glpc and t i c analysis of t h i s o i l and the a c i d i f i e d crude reaction mixture f a i l e d to indicate any of the desired product, methyl 3,5-dioxohexanoate (176a). D i s t i l l a t i o n of the o i l at reduced pressure gave 0.521 g (90%) of methyl acetoacetate, bp 51-52°C (17 mm) i d e n t i f i e d by glpc analysis and comparison of i t s i r and nmr spectra with those of authentic material. i i ) Attempted acylation with methyl benzoate. t Diisopropylamine (1.536 g, 15.0 mmole) was weighed into an oven-dried f l a s k , and tetrahydrofuran (ca. 25 ml) was d i s t i l l e d d i r e c t l y into t h i s f lask from lithiu m aluminium hydride. The flask was equipped with a magnetic s t i r r e r , stoppered (septum cap), cooled i n ice and flushed with nitrogen. n-Butyllithium, as a 2.1M solution i n hexane, (7.5 ml, 15.8 mmole) was added dropwise to the cooled solution and the reaction allowed to stand for ten minutes afte r the addition was complete. Methyl acetoacetate (0.580 g, 5.0 -149-mmole) was added t o t h e r e a c t i o n o v e r a p e r i o d o f about t e n minutes and a f u r t h e r p e r i o d o f t e n m i n u t e s a l l o w e d t o e l a p s e b e f o r e m e t h y l benzoate (0.680 g, 5.0 mmole) was added. A f t e r t e n minutes t h e r e a c t i o n was quenched w i t h c o n c e n t r a t e d h y d r o c h l o r i c a c i d ( ca. 4 ml) and t h e r e a c t i o n worked up by the a d d i t i o n o f e t h e r (35 ml) and wa t e r (10 m l ) . The aqueous phase was s e p a r a t e d and f u r t h e r e x t r a c t e d w i t h e t h e r (2 x 35 m l ) . The e t h e r e a l e x t r a c t s were combined, washed w i t h water (3 x 20 ml) and w i t h s a t u r a t e d sodium c h l o r i d e s o l u t i o n (2 x 20 m l ) , d r i e d o v e r anhydrous sodium s u l p h a t e and f i l t e r e d . The s o l v e n t s were removed by e v a p o r a t i o n under r e d u c e d p r e s s u r e and t h e r e s u l t i n g y e l l o w o i l c r y s t a l l i s e d on s t a n d i n g o v e r n i g h t . R e c r y s t a l l i s a t i o n from e t h e r gave 0.924 118 g (91%) o f N , N - d i i s o p r o p y l b e n z a m i d e mp 68-69°C ( l i t mp 69-71°C). i r (CHC1 3) 1620 c m - 1 ( C = 0 ) ; nmr (CDC1 3) 67.30 ( s , 5, a r y l p r o t o n s ) , 3.67 ( s e p t u p l e t , J=6Hz, 2, N ( C H M e 2 ) 2 ) , and 1.32 ppm (d, H=6Hz, 12, N (CH (CH 3) 2) 2) . G l p c and t i c a n a l y s i s o f t h e c r u d e o i l f a i l e d t o show any o f the d e s i r e d p r o d u c t s m e t h y l 3 , 5 - d i o x o - 5 - p h e n y l p e n t a n o a t e (176d) o r 3 , 5 - d i o x o - 5 - p h e n y l p e n t a n o i c a c i d (178d). b) L i t h i u m N - c y c l o h e x y l - N - i s o p r o p y l a m i d e . ( i ) A c y l a t i o n w i t h m e t h y l a c e t a t e . N - C y c l o h e x y l - N - i s o p r o p y l a m i n e , w h i c h had been d i s t i l l e d from c a l c i u m h y d r i d e and s t o r e d o v e r p o t a s s i u m h y d r o x i d e u n t i l u s e d , (2.130 g, 15.0 mmole) was weighed i n t o -150-an oven d r i e d f l a s k and t o t h i s was added 2 , 2 ' - b i p y r i d y l (ca. 10 mg). T e t r a h y d r o f u r a n (ca. 25 ml) was d i s t i l l e d d i r e c t l y i n t o t h i s f l a s k from l i t h i u m a l u m i n i u m h y d r i d e . The f l a s k was equipped w i t h a magnetic s t i r r e r , s t o p p e r e d (septum c a p ) , c o o l e d i n i c e , and f l u s h e d w i t h n i t r o g e n . S u f f i c i e n t n - b u t y l l i t h i u m s o l u t i o n was added t o t h e r e a c t i o n t o produce a permanent r e d c o l o u r a t i o n , and t h e n t h e measured volume o f n - b u t y l l i t h i u m (6 ml o f a 2.5M s o l u t i o n i n hexane, 15.0 mmole) was added d r o p w i s e t o t h e r e a c t i o n m i x t u r e . A f t e r a p e r i o d o f t e n mi n u t e s had e l a p s e d , m e t h y l a c e t o a c e t a t e (0.581 g, 5.0 mmole) was added d r o p w i s e and t h e r e a c t i o n a l l o w e d t o s t a n d f o r twenty m i n u t e s b e f o r e t h e m e t h y l a c e t a t e (0.371 g, 5.0 mmole) was added. A f t e r a f u r t h e r twenty minutes t h e r e a c t i o n was quenched w i t h c o n c e n t r a t e d h y d r o c h l o r i c a c i d ( ca. 4 ml) and worked up by t h e a d d i t i o n o f e t h e r (35 ml) and water (10 m l ) . The aqueous phase was s e p a r a t e d and f u r t h e r e x t r a c t e d w i t h e t h e r (2 x 35 m l ) . The e t h e r e a l e x t r a c t s were combined, washed w i t h water (2 x 20 ml) and w i t h s a t u r a t e d sodium c h l o r i d e s o l u t i o n (2 x 20 m l ) , d r i e d o v e r anhydrous sodium s u l p h a t e and f i l t e r e d . The s o l v e n t s were removed by e v a p o r a t i o n under r e d u c e d p r e s s u r e t o g i v e 0.537 g o f y e l l o w o i l . G l p c a n a l y s i s o f t h i s o i l ( c o l C, 120°C) showed i t t o c o n t a i n m e t h y l a c e t o a c e t a t e and m e t h y l 3,5-dioxohexanoate (176a) i n t h e r a t i o n 93:7. D i s t i l l a t i o n o f t h e o i l a t r e d u c e d p r e s s u r e gave 0.486 g (88%) o f m e t h y l a c e t o a c e t a t e bp 49-52°C (17 mm), i d e n t i f i e d by comparison o f i r and nmr s p e c t r a -151-w i t h t h o s e o f a u t h e n t i c m a t e r i a l , and 40 mg o f r e s i d u e . The r e s i d u e was d i s t i l l e d i n a b u l b - t o - b u l b d i s t i l l a t i o n a p p a r a t u s (bath t e m p e r a t u r e 50°C) under h i g h vacuum (0.2 mm) t o g i v e 37 mg (4%) o f m e t h y l 3,5-dioxohexanoate (176a) w h i c h was i d e n t i f i e d by comparison w i t h p r e v i o u s l y p r e p a r e d m a t e r i a l by g l p c ( c o l C, 120°C) and t i c . ( i i ) A c y l a t i o n w i t h m e t h y l b e n z o a t e . N - C y c l o h e x y l - N - i s o p r o p y l a m i n e , w h i c h had been d i s t i l l e d from c a l c i u m h y d r i d e and s t o r e d o v e r p o t a s s i u m h y d r o x i d e u n t i l u s e d , (2.130 g, 15.0 mmole) was weighed i n t o an oven d r i e d f l a s k and t o t h i s was added 2 , 2 ' - b i p y r i d y l ( c a . 10 mg). T e t r a h y d r o f u r a n ( c a . 25 ml) was d i s t i l l e d d i r e c t l y i n t o t h i s f l a s k from l i t h i u m a l u m i n i u m h y d r i d e . The f l a s k was equipped w i t h a magnetic s t i r r e r , s t o p p e r e d (septum c a p ) , c o o l e d i n i c e , and f l u s h e d w i t h n i t r o g e n . S u f f i c i e n t n-b u t y l l i t h i u m s o l u t i o n was added t o t h e r e a c t i o n t o produce a permanent r e d c o l o u r a t i o n , and t h e n t h e measured volume o f n - b u t y l l i t h i u m (6 ml o f a 2.5M s o l u t i o n i n hexane, 15.0 mmole) was added d r o p w i s e t o t h e r e a c t i o n m i x t u r e . A f t e r a p e r i o d o f t e n minutes had e l a p s e d , m e t h y l a c e t o a c e t a t e (0.581 g, 5.0 mmole) was added d r o p w i s e and t h e r e a c t i o n a l l o w e d t o s t a n d f o r twenty m i n u t e s b e f o r e t h e m e t h y l b e n z o a t e (0.680 g, 5.0 mmole) was added. A f t e r a f u r t h e r twenty m i n u t e s th e r e a c t i o n was quenched w i t h c o n c e n t r a t e d h y d r o c h l o r i c a c i d (ca. 4 ml) and worked up by t h e a d d i t i o n o f e t h e r (35 ml) and -152-water (10 m l ) . The aqueous phase was s e p a r a t e d and f u r t h e r e x t r a c t e d w i t h e t h e r (2 x 35 m l ) . The e t h e r e a l e x t r a c t s were combined, washed w i t h w a t e r (3 x 20 ml) and w i t h s a t u r a t e d sodium c h l o r i d e s o l u t i o n (2 x 20 m l ) , d r i e d o v e r anhydrous sodium s u l p h a t e and f i l t e r e d . The s o l v e n t s were removed by e v a p o r a t i o n under r e d u c e d p r e s s u r e t o g i v e a y e l l o w semi-c r y s t a l l i n e m a t e r i a l . R e c r y s t a l l i s a t i o n from e t h e r gave 1.080 g (88%) o f N - c y c l o h e x y l - N - i s o p r o p y l b e n z a m i d e (196) , mp 76-78 C, w h i c h was c h a r a c t e r i s e d as o u t l i n e d below. The mother l i q u o r s from t h e r e c r y s t a l l i s a t i o n were f o u n d , by g l p c a n a l y s i s , ( c o l C, 200 C) t o c o n t a i n m e t h y l 3,5-dioxo-5-p h e n y l p e n t a n o a t e (176d) and were s u b j e c t e d t o chromatography on s i l i c a g e l , u s i n g c h l o r o f o r m as e l u e n t . The major component i s o l a t e d from t h i s chromatography was m e t h y l 3,5-dioxo-5-p h e n y l p e n t a n o a t e (176d), (0.085 g, 8 % ) , i d e n t i f i e d by c o m p a r i s o n of i t s i r spectrum w i t h t h a t o f p r e v i o u s l y p r e p a r e d m a t e r i a l . N - c y c l o h e x y l - N - i s o p r o p y l b e n z a m i d e was c h a r a c t e r i s e d by: i r (CHC1 3) 1620 c m - 1 ( C = 0 ) ; nmr {CClk) 67.30 ( s , 5, a r y l p r o t o n s ) , 3.87 - 3.00 (m, 2, N ( C H 3 ) 2 ) , 2.20 - 1.00 (m, 10, p r o t o n s on C 2 - C 6 o f c y c l o h e x y l r i n g ) and 1.30 ppm (d, H=6Hz, 6, N C ( C H 3 ) 2 ) ; mass spectrum m/e ( r e l i n t e n s i t y ) 2 4 6 ( 2 2 ) , 2 4 5 ( 3 7 ) , 244 ( 1 4 ) , 230 ( 2 2 ) , 203 ( 2 7 ) , 202 ( 4 6 ) , 189 ( 1 5 ) , 188 ( 3 9 ) , 165 ( 1 1 ) , 1 6 4 ( 3 7 ) , 163 ( 5 4 ) , 1 6 2 ( 6 2 ) , 149 ( 1 1 ) , 148 ( 4 1 ) , 146 ( 2 3 ) , 1 4 5 ( 3 2 ) , 129 ( 1 9 ) , 128 ( 1 9 ) , 118 ( 3 6 ) , 117 ( 4 1 ) , 115 ( 3 3 ) , 1 0 5 ( 7 2 ) , 103 ( 3 5 ) , 85 ( 3 3 ) , 79 (3 5 ) , 78 ( 4 4 ) , 76 ( 9 3 ) , 56 (83) and 54 (100). -153-C o n d e n s a t i o n o f t h e sodium s a l t o f m e t h y l a c e t o a c e t a t e w i t h d i a n i o n 132. a) A t room t e m p e r a t u r e , a c i d q u e n c h i n g . Sodium h y d r i d e , as a 57% m i n e r a l o i l d i s p e r s i o n , ; (0.466 g, 11.0 mmole) was weighed i n t o an oven d r i e d f l a s k , and f r e e d from m i n e r a l o i l by washing w i t h hexane ( c a . 15 ml) and d e c a n t a t i o n . The washing p r o c e d u r e was r e p e a t e d t w i c e w i t h hexane and t h e r e s i d u a l hexane was removed by washing w i t h t e t r a h y d r o f u r a n . A f t e r d e c a n t a t i o n o f t h e t e t r a h y d r o f u r a n , f r e s h t e t r a h y d r o f u r a n was d i s t i l l e d d i r e c t l y i n t o t h e f l a s k , from l i t h i u m a l u m i n i u m h y d r i d e . The f l a s k was equipped w i t h a magnetic s t i r r e r , s t o p p e r e d (septum c a p ) , c o o l e d i n i c e and f l u s h e d w i t h n i t r o g e n . M e t h y l a c e t o a c e t a t e (1.162 g, 10.0 mmole) was added d r o p w i s e t o t h e c o o l e d s l u r r y , and a f t e r t h e a d d i t i o n was complete t h e r e a c t i o n was a l l o w e d t o 'stand f o r a p e r i o d o f about t e n m i n u t e s . n - B u t y l l i t h i u m , as a 2.3M s o l u t i o n i n hexane, (2.2 m l , 5.1 mmole) was added d r o p w i s e t o t h e r e a c t i o n , w h i c h was th e n a l l o w e d t o warm t o room t e m p e r a t u r e . A f t e r a p e r i o d o f twenty f o u r hours t h e r e a c t i o n was quenched by a d d i t i o n o f c o n c e n t r a t e d h y d r o c h l o r i c a c i d ( c a. 1.5 ml) and worked up by a d d i t i o n o f e t h e r (35 ml) and w a t e r (5 m l ) . The aqueous phase, t h e pH o f w h i c h was c a . 2, was s e p a r a t e d and f u r t h e r e x t r a c t e d w i t h e t h e r (2 x 35 m l ) . The e t h e r e a l e x t r a c t s were combined, washed w i t h s a t u r a t e d sodium c h l o r i d e s o l u t i o n (4 x 20 m l ) , d r i e d o v e r anhydrous -154-sodium s u l p h a t e and f i l t e r e d . The s o l v e n t s were removed by e v a p o r a t i o n under reduc ed p r e s s u r e t o g i v e 0.983 g o f brown o i l . D i s t i l l a t i o n o f t h i s o i l a t r e d u c e d p r e s s u r e gave 0.716 g (62%) o f m e t h y l a c e t o a c e t a t e , bp 45-47°C (14 nm), i d e n t i f i e d by comparison o f i t s i r and nmr s p e c t r a w i t h t h o s e o f a u t h e n t i c m a t e r i a l , and a brown s o l i d r e s i d u e w h i c h was c r y s t a l l i s e d from methanol t o g i v e 0.220 g (24%) o f m e t h y l o r s e l l i n a t e (183) , mp 138-140°C ( l i t 1 1 9 , mp 138-139°C), mixed mp 138-140°C. i r (CHC1 3) 3650 (Free OH), 3300 (hydrogen bonded OH), 1655 ( f r e e C=0) and 1620 cm - 1 (hydrogen bonded C=0); nmr (CDC1 3) 66.30 ( s , 2, a r y l p r o t o n s ) , 6.10 (broad s, exchangeable D 20, 2, OH), 3.95 ( s , 3, OCH 3) and 2.50 ppm ( s , 3, C H 3 ) . b) A t room t e m p e r a t u r e , b u f f e r e d q u e n c h i n g . T h i s r e a c t i o n was performed i n t h e same manner as t h e p r e c e d i n g r e a c t i o n . The r e a g e n t s employed were: sodium h y d r i d e , as a 57% m i n e r a l o i l d i s p e r s i o n , (0.463 g, 11.0 mmole), m e t h y l a c e t o a c e t a t e (1.160 g, 10.0 mmole) and n - b u t y l l i t h i u m , as a 2.1M s o l u t i o n i n hexane, (2.5 m l , 5.2 mmole). A f t e r t h e twenty f o u r hour r e a c t i o n p e r i o d , t h e r e a c t i o n was quenched by a d d i n g i t , v i a a s t a i n l e s s s t e e l c a n n u l a , t o a v i g o r o u s l y s t i r r e d m i x t u r e o f e t h e r (50 ml) and b u f f e r s o l u t i o n ( p r e p a r e d by d i s s o l v i n g sodium d i h y d r o g e n o r t h o p h o s p h a t e (4 g) and d i s o d i u m hydrogen o r t h o p h o s p h a t e -155-(4 g) i n water (20 ml). The aqueous phase was separated, saturated with sodium chloride and further extracted with ether (3 x 20 ml). The ethereal layers were combined, washed with saturated sodium chloride solution (20 ml), dried over anhydrous sodium sulphate and f i l t e r e d . The solvents were removed by evaporation under reduced pressure and the r e s u l t i n g o i l chromatographed on s i l i c a g e l , using a mixture of benzene and ethyl acetate (1:1 v/v) as eluent. Three components were obtained from the chromatography, and these, i n order of t h e i r e l u t i o n , were: methyl 3,5,7-trioxooctanoate (182) , (83 mg, 8%) as a pale yellow, unstable o i l , which on standing overnight at 0°C was converted to methyl o r s e l l i n a t e i n quantitative y i e l d , , and was characterised as outlined below, methyl o r s e l l i n a t e (183) (155 mg, 17%) as cream coloured needles, mp 138-140°C, i d e n t i f i e d by comparison of i t s i r spectrum with that of authentic material, and methyl acetoacetate (0.679 g, 59%) i d e n t i f i e d by comparison of i t s i r spectrum with that of authenticcmaterial. Methyl 3,5,7-trioxooctanoate was characterised by: i r (CHC13) 3400 (enol OH), 1740 (ester C=0), 1720 (C=0), 1640 (C=C-C=0), 1620 (HO-C=C-C=0) and 1600 cm"l (C=C); nmr (CCI4) 614.60 (broad s, exchangeable D 2 0 , 1.1, enol O-H), 6.20 (m, 1.1, C=CH), 3.96 (s, 3, 0 C H 3 ) , 3.70 (s, 4, C0CH_2C02Me) , 3.67 (s, 1.8, COCH^CO) and 2.43 ppm (s, 3, C0CH 3 ) mass spectrum m/e ( r e l intensity) 184 (9), 182 (4), 151(4), -156-150(13) , 143 (7) , 142 (26) , 127 (40) , 117 ( 9 ) , 113 (27) , 101 (9) , 1 0 0 ( 2 4 ) , 85 (1 0 0 ) , 73 (2 1 ) , 69 ( 2 0 ) , 61.(34),and 43 (100). c) A t r e f l u x t e m p e r a t u r e . Sodium h y d r i d e , as a 57% m i n e r a l o i l d i s p e r s i o n , (0.465 g, 11.0 mmole) was weighed i n t o an oven d r i e d f l a s k , and f r e e d from m i n e r a l o i l by washing w i t h hexane and t e t r a h y d r o f u r a n as p r e v i o u s l y o u t l i n e d . A f t e r r e m o v a l o f t h e s o l v e n t s used i n t h e w a s h i n g , f r e s h t e t r a h y d r o f u r a n was d i s t i l l e d i n t o t h e f l a s k f r om l i t h i u m a l u m i n i u m h y d r i d e . The f l a s k was equipped w i t h a magnetic s t i r r e r , s t o p p e r e d (septum c a p ) , c o o l e d i n i c e and f l u s h e d w i t h n i t r o g e n . M e t h y l a c e t o a c e t a t e (1.161g, 10.0 mmole) was added d r o p w i s e t o t h e c o o l e d s l u r r y , and a f t e r t h e a d d i t i o n was c o m p l e t e , t h e r e a c t i o n was a l l o w e d t o s t a n d f o r a p e r i o d o f t e n m i n u t e s . n - B u t y l l i t h i u m , as a 2.3M s o l u t i o n i n hexane, (2.2 m l , 5.1 mmole) was added d r o p w i s e t o t h e r e a c t i o n , w h i c h was t h e n a l l o w e d t o warm t o room t e m p e r a t u r e . The f l a s k was t h e n t r a n s f e r r e d t o a g l o v e b ag, where, under an atmosphere o f n i t r o g e n , t h e septum cap was removed and r e p l a c e d w i t h a r e f l u x c o n d e n s e r , t h e t o p o f w h i c h was s t o p p e r e d w i t h a f r e s h septum cap. The f l a s k and condenser assembly was wi t h d r a w n from t h e g l o v e bag and heated t i l l a moderate r a t e o f r e f l u x was o b t a i n e d . A f t e r two hours a t r e f l u x t e m p e r a t u r e , t h e h e a t i n g was d i s c o n t i n u e d and t h e f l a s k c o o l e d i n i c e t o 0°C. The r e a c t i o n was quenched w i t h c o n c e n t r a t e d h y d r o c h l o r i c a c i d -157-(ca. 1.5 ml) and worked up by t h e a d d i t i o n o f e t h e r (35 ml) and w a t e r (5 m l ) . The aqueous phase was s e p a r a t e d and f u r t h e r e x t r a c t e d w i t h e t h e r (2 x 35 m l ) . The e t h e r e a l e x t r a c t s were combined, washed w i t h s a t u r a t e d sodium c h l o r i d e s o l u t i o n (4 x 20 m l ) , d r i e d o v e r anhydrous sodium s u l p h a t e and f i l t e r e d . The s o l v e n t s were removed by e v a p o r a t i o n under reduced p r e s s u r e , and d i s t i l l a t i o n o f t h e r e s u l t i n g o i l a t reduced p r e s s u r e gave 0.821 g (71%) o f m e t h y l a c e t o a c e t a t e , bp 46-48°C (14 mm), i d e n t i f i e d by c o m p a r i s o n o f i t s i r spectrum w i t h t h a t o f a u t h e n t i c m a t e r i a l , and a brown r e s i d u e , w h i c h on t i t r a t i o n w i t h methanol gave 0.213 g (23%) o f m e t h y l o r s e l l i n a t e (183) , as p a l e y e l l o w n e e d l e s , i d e n t i f i e d by comparison o f i t s ^ i r spectrum w i t h t h a t o f a u t h e n t i c m a t e r i a l . A l k y l a t i o n o f t h e D i a n i o n o f B e t a - k e t o e s t e r s w i t h d i h a l o -a l k a n e s . R e a c t i o n o f 1,3-dibromopropane w i t h d i a n i o n 132. a) W i t h 1 e q u i v a l e n t o f 1,3-dibromopropane. Sodium h y d r i d e , as a 57% m i n e r a l o i l d i s p e r s i o n , (0.465 g, 11.0 mmoles) was weighed i n t o an oven d r i e d f l a s k , and t e t r a h y d r o f u r a n ( c a. 25 ml) d i s t i l l e d d i r e c t l y i n t o t h i s f l a s k , from l i t h i u m a l u m i n i u m h y d r i d e . The f l a s k was equipped w i t h a magnetic s t i r r e r , s t o p p e r e d (septum c a p ) , c o o l e d i n i c e and f l u s h e d w i t h n i t r o g e n . M e t h y l a c e t o a c e t a t e (1.161 g, 10.0 mmole) was added d r o p w i s e t o t h e c o o l e d s l u r r y and t h e -158-reaction allowed to stand for ten minutes afte r the addition was complete. n-Butyllithium, as a 2.3M solution i n hexane, (4.5 ml, 10.6 mmole) was added dropwise to the reaction which was allowed to stand f o r a further ten minutes before the addition of 1,3-dibromopropane (2.022 g, 10.0 mmole) i n one portion. After a f i n a l period of ten minutes, the reaction was quenched with concentrated hydrochloric acid (2 ml) and worked up by the addition of ether (35 ml) and water (10 ml). The aqueous phase was separated and further extracted with ether (2 x 35 ml). The ethereal extracts were combined, washed with saturated sodium chloride solution (4 x 25 ml), dried over anhydrous sodium sulphate and f i l t e r e d . The solvents were removed by evaporation under reduced pressure and the r e s u l t i n g yellow o i l chromatographed on s i l i c a g el using chloroform as eluent. Tv/o components were i s o l a t e d from t h i s chromatography, and these were, i n order of e l u t i o n , methyl 2-oxocyclohexanecarboxylate (145) (0.515 g, 33%), i d e n t i f i e d by comparison of i t s i r and nmr spectra with those of previously prepared material and by t i c comparison, and dimethyl 3,9-dioxoundecanedioate (187a) (0. 503 g, 37%), bp 117-119°C (0.2 mm), which was characterised by: i r (CHC13) 1745 (ester C=0) and 1720 cm - 1 (C=0); nmr (CDC13) 63.76 (s, 6, 0CH 3), 3.43 (s, 4, C0CH 2C0 2Me), 2.37 (t, J=6Hz, 4, COCH_2CH2) and 1.93 - 1.10 ppm (m, 6, COCH2CH2CH2CH2CH2CO); -159-mass spectrum m/e ( r e l intnesity) 254 (65), 241(3), 222(5), 209(3) , 167(85) , 157(55), 139(17), 129(16), 121(50), 116 (39), 101(25), 82(68), 59(40), 55(58) and 43(10Q); analysis calcd for C 1 3H 2o06: C 57.34 H 7.40 found: C 57.03 H 7.29 b) With 0.5 equivalents of 1,3-dibromopropane. This reaction was performed i n the same manner as the previous experiment i n which dibromopropane and the dianion of methyl acetoacetate were reacted. The reagents used were: sodium hydride, as a 57% mineral o i l dispersion, (0.466 g, 11.0 mmole), methyl acetoacetate (1.160 g, 11.0 mmole), n-butyllithium, as a 2.3M solution i n hexane, (4.5 ml, 10.6 mmole) and 1,3-dibromopropane (1.012 g, 5.0 mmole), which gave 1.049 g (77%) of dimethyl 3,9-diouxoundecanedioate (187a), i s o l a t e d by d i s t i l l a t i o n . This product had i d e n t i c a l i r and nmr spectra as that prepared previously. c) D i l u t i o n study. A solution of dianion 132 was prepared as outlined below: Sodium hydride, as a 57% mineral o i l dispersion, (0.465 g, 11.0 mmole) was weighed into an oven dried f l a s k , and tetrahydrofuran (ca. 25 ml) d i s t i l l e d d i r e c t l y into t h i s f l a s k , from l i t h i u m aluminium hydride. The f l a s k was equipped with -160-a magnetic s t i r r e r , stoppered (septum cap), cooled i n i c e and flushed with nitrogen. Methyl acetoacetate (1.161 g, 10.0 mmole) was added dropwise to the cooled s l u r r y and the reaction allowed to stand for ten minutes a f t e r the addition was complete. n-Butyllithium, as a 2.3M solution i n hexane, (4.5 ml, 10.6 mmole) was added dropwise to the reaction which was allowed to warm to room temperature. 1,3-Dibromopropane (2.023 g, 10.0 mmole) was weighed into an oven dried f l a s k and tetrahydrofuran' (ca. 25 ml) was d i s t i l l e d d i r e c t l y into t h i s f l a s k from lithium aluminium hydride and the flask stoppered with a septum cap. A 250 ml fla s k was equipped with a Soxlet extraction apparatus which ca r r i e d a three necked adaptor and a ref l u x condenser. The assembly was flame-dried, a f t e r which the condenser was f i t t e d with a calcium chloride drying tube and the two remaining openings stoppered with septum caps. Tetrahydrofuran (ca. 50 ml) was placed i n the apparatus by means of a syringe, and the flask heated to produce a moderate rate of r e f l u x . The solutions of dianion and bromopropane were then added to the Soxlet extractor, v i a st a i n l e s s s t e e l cannulae, at > such a rate that one drop of each solution was added to each cycle of the extractor. The rate of addition was cont r o l l e d by applying nitrogen pressure to the fl a s k s containing the solutions. After the addition was complete, r e f l u x was maintained for several more cycles to ensure a l l of the reagents were transferred to the f l a s k . The apparatus was -161-allowed to cool before the reaction was quenched with concentrated hydrochloric acid (2 ml). Water (10 ml) was added and the aqueous phase separated and extracted with ether (2 x 35 ml). The organic phases weye combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulphate and f i l t e r e d . The solvents were removed by evaporation under reduced pressure and the r e s u l t i n g o i l d i s t i l l e d , also under reduced pressure, to give 1.059 g (68%) of methyl 2-oxocyclohexanecarboxylate (145) which was i d e n t i f i e d by comparison of i t s i r and nmr spectra with those of previously prepared material. The residue from the d i s t i l l a t i o n was chromatographed on s i l i c a gel using chloroform as eluent to give 0.149 g (11%) of dimethyl 3,9-dioxoundecanedioate (147a), which was i d e n t i f i e d by comparison of i t s i r and nmr spectra with those of previously prepared material. Methyl 2-(2-carbomethoxy-3-oxocyclohex-l-enyl)-acetate (188). This compound was prepared by the same procedure as that employed i n the reaction of 1 equivalent of 1,3-dibromopropane with dianion 132. The reagents used were: sodium hydride, as a 57% mineral o i l dispersion, (0.466 g, 11.0 mmole), methyl acetoacetate (1.161 g, 10.0 mmole), n-butyllithium, as a 2.1M solution i n hexane, (5.0 ml, 10.5 mmole) and dibromomethane (0.872 g, 5.0 mmole), which gave 0.701 g (62%) of 188, bp 75-78°C (0.2 mm) characterised by: -162-i r (CHCI3) 3600 (broad, enol OH), 1740 (ester C=0), 1735 (C=C-CO Me) and 1680 cm-1 (C=C-C=0); uv (CH3OH) 228 nm (1.2 x 10 ); nmr (CDC13) 63.83 (s, 3, C=C-C0 2CH 3), 3.75 (s, 3, C0 2CH 3), 3.35 (s, 2, CH2C02Me) and 2.40 - 1.70 ppm (m, 6, cyclohexenyl protons); mass spectrum m/e ( r e l intensity) 226(19), 195(43), 194(100), 166(45), 162(100), 138 (40), 129 (23), 112(24), 107 (28), 101 (21), 82 (38), 79 (48), 70 (46), 59 (51) and 43(57); analysis calcd f o r CnH^Os: C 58.40 H 6.24 found : C 58.53 H 6.24 Dimethyl 3,16-dioxooctadecanedioate (187b). This compound was prepared by the same procedure as that employed i n the reaction of 1 equivalent of 1,3-dibromopropane with dianion 132. The reagents used were: sodium hydride, as a 57% mineral o i l dispersion, (0.465 g, 11.0 mmole), methyl acetoacetate (1.162 g, 10.0 mmole), n-butyllithium, as a 2.1M solution i n hexane, (5.0 ml, 10.5 mmole) and 1,10-dibromodecane (1.501 g, 5.0 mmole). The crude product from t h i s reaction s o l i d i f i e d on standing overnight and was subsequently r e c r y s t a l l i s e d from ether to give 1.516 g, (98%) of 187b, mp 80-82°C. i r (CHCI3) 1745 (ester OO) and 1720 cm"1 (C=0) ; 'N nmr (CC14) 63.50 (s, 6, OCH3) , 3.27 (s, 4, COCH2C0 2Me) , 2.43 (t, H=6Hz, 4, COCH2CH2) and 1.27 ppm (m, 20, COCH2 (CH2) 10 CH2CO); -163-mass spectrum m/e ( r e l i n t e n s i t y ) 3 7 0 ( 1 0 ) , 3 3 9 ( 1 3 ) , 338 (12) , 320(16) , 296 ( 2 0 ) , 2 6 5 ( 1 8 ) , 256 ( 1 7 ) , 2 5 5 ( 1 0 0 ) , 237 ( 2 1 ) , 223 ( 1 4 ) , 205 (12) , 195 (11) , 181 (23) , 178 (14) , 163 ( 2 7 ) , 1 5 8 ( 1 2 ) , 143 ( 9 ) , 129 ( 7 1 ) , 116 ( 9 0 ) , 1 0 1 ( 5 1 ) , 69 ( 5 8 ) , 59 (95) and 43 (65) ; a n a l y s i s c a l c d f o r C 2 o H 3 4 0 6 : C 64.84 H 9.25 found: C 64.72 H 9.28 C o n d e n s a t i o n o f N i t r i l e s w i t h t h e D i a n i o n o f g - K e t o e s t e r s . C o n d e n s a t i o n o f B e n z o n i t r i l e w i t h d i a n i o n 132. Sodium h y d r i d e , as a 57% m i n e r a l o i l d i s p e r s i o n , (0.467 g, 11.0 mmole) was weighed i n t o a 50 ml oven d r i e d f l a s k and t e t r a h y d r o f u r a n ( ca. 25 ml) was d i s t i l l e d d i r e c t l y i n t o t h i s f l a s k from l i t h i u m a l u m i n i u m h y d r i d e . The f l a s k was equipped w i t h a magnetic s t i r r e r , s t o p p e r e d (septum c a p ) , c o o l e d i n i c e and f l u s h e d w i t h n i t r o g e n . M e t h y l a c e t o a c e t a t e (1.160 g, 10.0 mmole) was added d r o p w i s e t o t h e c o o l e d s l u r r y and t h e r e a c t i o n a l l o w e d t o s t i r f p r t e n mi n u t e s a f t e r t h e a d d i t i o n was complete. n - B u t y l l i t h i u m , as a 2.1M s o l u t i o n i n hexane, (5 m l , 10.5 mmole) was added d r o p w i s e t o t h e r e a c t i o n and a f t e r t e n minutes b e n z o n i t r i l e (1.031 g, 10.0 mmole) was added. The r e a c t i o n m i x t u r e was a l l o w e d t o warm t o room t e m p e r a t u r e and s t i r r e d f o r t w e l v e hours b e f o r e b e i n g quenched w i t h c o n c e n t r a t e d h y d r o c h l o r i c a c i d (2 m l ) . The r e a c t i o n was worked up by t h e a d d i t i o n o f e t h e r (35 ml) and wat e r (10 ml) and t h e r e s u l t i n g p r e c i p i t a t e f i l t e r e d o f f . -164-The p r e c i p i t a t e was washed w i t h a c e t o n e (2 x 10 m l ) , a i r d r i e d and s u b l i m e d a t 150°C (0.2 mm) t o g i v e 0.547 g (29%) o f 6 - p h e n y l p y r i d i n e - 2 , 4 - d i o n e (191a) as c o l o u r l e s s s p a r s , c h a r a c t e r i s e d as o u t l i n e d below. The aqueous phase o f t h e f i l t r a t e was s e p a r a t e d and f u r t h e r e x t r a c t e d w i t h e t h e r (2 x 35 m l ) . The e t h e r e a l e x t r a c t s were combined, washed w i t h s a t u r a t e d sodium c h l o r i d e s o l u t i o n (6 x 15 m l ) , d r i e d o v e r anhydrous sodium s u l p h a t e and f i l t e r e d . The s o l v e n t s were removed by e v a p o r a t i o n under r e d u c e d p r e s s u r e and t h e r e s u l t i n g o i l chromatographed on s i l i c a g e l u s i n g e t h y l a c e t a t e as e l u e n t . The major f r a c t i o n from t h i s chromatography was c o l l e c t e d , and f r e e d from e l u e n t by d i s t i l l a t i o n a t room t e m p e r a t u r e under reduced p r e s s u r e t o g i v e 1.466 g (66%) o f m e t h y l 5-amino-3-oxo-5-phenylpent-4-enoate (194a) as a p a l e y e l l o w o i l . i r (CHC1 3) 3550 (N-H), 1740 ( e s t e r C=0), 1615 (0=C-C=C-NH 2) and 1600 cm"* (C=C); uv (C 2H 5OH) 325 nm; nmr (CClh) 6 8.00 (broad s, exchangeable D 20, 1, hydrogen bonded NH), 7.41 (m, 5, a r o m a t i c p r o t o n s ) , 6.20 (broad s, exchangeable D 20, 1, NE), 5.37 ( s , 1, C=CH), 3.60 ( s , 3, OCH 3) and 3.27 ppm ( s , 2, COCH^C0 2Me) ; mass spectrum a) h i g h r e s o l u t i o n c a l c d f o r C 1 2 H 1 3 N 0 3 : 219.0895 amu, found 219.0896 m/e; b) low r e s o l u t i o n m/e ( r e l i n t e n s i t y ) 219 ( 2 6 ) , 159 ( 1 5 ) , 146 ( 4 7 ) , 127 ( 3 5 ) , 121 ( 3 2 ) , 119 ( 9 5 ) , 118 ( 9 5 ) , -165-103 ( 3 0 ) , 84 (52) , 82(22) , 59 (46) and 43 (100). 6 - P h e n y l p y r i d i n e - 2 , 4 - d i o n e (191) was c h a r a c t e r i s e d by: mp 314-316°C ( l i t 1 1 6 mp 315-318°C).; i r (KBr d i s c ) 1640, 1620, 1595 and 1560 cm" 1; uv (C2H5OH) 310 and 255 nm, (C 2H 5OH + NaOH) 240 nm; mass spectrum m/e ( r e l i n t e n s i t y ) 1 8 8 ( 1 6 ) , 1 8 7 ( 1 0 0 ) , 186 ( 1 7 ) , 160 ( 6 ) , 159 ( 1 5 ) , 158 ( 1 0 ) , 147 ( 1 1 ) , 146 ( 6 1 ) , 130 ( 1 9 ) , 104 ( 3 3 ) , 103 ( 3 3 ) , 9 1 ( 1 4 ) , 77 ( 2 1 ) , 69 (9) and 5 1 ( 1 5 ) . T h e r m o l y s i s o f M e t h y l 5-amino-3-oxo-5-phenylpent-4-enoate (194a). Enamine 194a (156 mg, 0.71 mmole) was p l a c e d i n a b u l b - t o - b u l b d i s t i l l a t i o n a p p a r a t u s and hea t e d t o 150°C under reduced p r e s s u r e (0.2 mm). A f t e r one h a l f hour t h e s t a r t i n g m a t e r i a l had c o m p l e t e l y d i s a p p e a r e d and w h i t e s p a r s had been d e p o s i t e d on t h e c o o l e r p a r t s o f t h e a p p a r a t u s . These c r y s t a l s were c o l l e c t e d and f o u n d : t o amount t o 134 mg (100%) o f 6 - p h e n y l p y r i d i n e - 2 , 4 - d i o n e ( 1 9 1 ) , w h i c h e x h i b i t e d i d e n t i c a l mp and i r and uv s p e c t r a t o t h a t o b t a i n e d p r e v i o u s l y . M e t h y l 5-amino-3-oxohex-4-enoate (194b) . Sodium h y d r i d e , as a 57% m i n e r a l o i l d i s p e r s i o n , (0.467 g, 11.0 mmole) was weighed i n t o a 50 ml oven d r i e d f l a s k and t e t r a h y d r o f u r a n ( c a. 25 ml) was d i s t i l l e d d i r e c t l y i n t o t h i s f l a s k from l i t h i u m a l u m i n i u m h y d r i d e . The f l a s k was equipped w i t h a magnetic s t i r r e r , s t o p p e r e d (septum c a p ) , -166-c o o l e d i n i c e and f l u s h e d w i t h n i t r o g e n . M e t h y l a c e t o a c e t a t e (1.160 g f 10.0 mmole) was added d r o p w i s e t o t h e c o o l e d s l u r r y and t h e r e a c t i o n a l l o w e d t o s t i r f o r t e n mi n u t e s a f t e r t h e a d d i t i o n was com p l e t e . n - B u t y l l i t h i u m , as a 2.1M s o l u t i o n i n hexane, (5 m l , 10.5 mmole) was added d r o p w i s e t o t h e r e a c t i o n and a f t e r t e n m i n u t e s a c e t o n i t r i l e (0.409 g, 10.0 mmole) was added. The r e a c t i o n m i x t u r e was a l l o w e d t o warm t o room t e m p e r a t u r e and s t i r r e d f o r s i x t e e n hours b e f o r e b e i n g quenched w i t h c o n c e n t r a t e d h y d r o c h l o r i c a c i d (2 m l ) . The r e a c t i o n was worked up by t h e a d d i t i o n o f e t h e r (35 ml) and water (10 m l ) . The aqueous phase was s e p a r a t e d and f u r t h e r e x t r a c t e d w i t h e t h e r (2 x 35 m l ) . The e t h e r e a l e x t r a c t s were combined, washed w i t h s a t u r a t e d sodium c h l o r i d e s o l u t i o n (4 x 15 m l ) , d r i e d o v e r anhydrous magnesium s u l p h a t e and f i l t e r e d . The s o l v e n t s were removed by e v a p o r a t i o n under r e d u c e d p r e s s u r e . The r e s u l t i n g s e m i - s o l i d was c r y s t a l l i s e d from c h l o r o f o r m t o g i v e 1.490 g (86%) o f 194b as l o n g y e l l o w n e e d l e s , mp 103-104°C. S u b l i m a t i o n a t 175°C (0.2 mm) gave c o l o u r l e s s s p a r s , b u t d i d not r a i s e t h e m e l t i n g p o i n t . i r (CHC13) 3550 (N-H), 1740 ( e s t e r C=0), 1625 (0=C-C=C-NH 2) and 1610 c m - 1 (C=C) ; uv (CH3OH) 303 nm (16.8 x 10 3) and (CH 3OH + NaOH) 274jnm; nmr (CDC1 3) 610.0 (broad s, exchangeable D 20, 1, hydrogen bonded N-H), 5.5 (broad s, exchan g e a b l e D 20, 1, NH), 5.10 ( s , 1, C=CH), 3.70 ( s , 3, OCH3), 3.33 ( s , 2, COCH 2C0 2Me) and 1.97 ppm ( s , 3, CCH3); -167-mass spectrum m/e (rel intensity) 158 (3)/ 157 (26), 126 (2), 125 (3), 85 (7), 84 (100), 83 (2), 70 (2), 68 (2), 54 (2), 43 (3) , 42 (5) and 41(4) ; analysis calcd for C7H11O3N: C 53.49 H 7.05 N 8.91 found: C 53.18 H 6.99 N 8.84 -168-B i b l i o g r a p h y . l a ) R.B. Woodward, W.A. A y e r , J.M. B e a t o n , F. B i c k e l h a u p t , R. B o n n e t t , P. Buchschacher, G.L. C r o s s , H. D u t l e r , J . Hannah, F.P. Hauck, S. I t o , A. Langermann, E. Le G o f f , W. 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Stern, Ed., "B e i l s t e i n s Handbuch der Organishen Chemie", B e r l i n (1927), v o l 10, p 414. -177-SPECTRAL APPENDIX The i r , nmr and mass spectra of a l l compounds, which have not been previously reported i n the l i t e r a t u r e , are shown i n t h i s appendix. -178--187--196--197--198--199--200-C O o LU L X ™ ^ 0 C H 3 162 a I 1 1—r—1—^—r—1 T t—1—1—1—1—1—1—1—1—1—1—1—1—1—1—1—1—1—1—1—1—1 D.D 50.0 10D.0 150.0 200.0 250.0 300.0 350.0 <100.0 M/E 4OD0 1 ^ too 0 Hi >-H> 4--201--210-UJ 0£ 0.0 I I I I , — r 50.0 100.0 ChUO 178e 150.0 200.0 M/E T 250.0 300.0 — I — r ~ 1 — i i f 350.0 400.0 2800 FREQUENCY (CM') 2400 2000 1800 1600 

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